U.S. patent number 10,087,195 [Application Number 15/314,006] was granted by the patent office on 2018-10-02 for certain protein kinase inhibitors.
This patent grant is currently assigned to CHONGQING FOCHON PHARMACEUTICAL CO., LTD., SHANGHAI FOCHON PHARMACEUTICAL CO., LTD.. The grantee listed for this patent is CHONGQING FOCHON PHARMACEUTICAL CO., LTD., Shanghai Fochon Pharmaceutical Co., Ltd.. Invention is credited to Zhifang Chen, Lihua Jiang, Tongshuang Li, Zhifu Li, Min Lin, Li Linghu, Qihong Liu, Yanxin Liu, Jing Sun, Haohan Tan, Qiang Tian, Weibo Wang, Xianlong Wang, Huajie Zhang, Weipeng Zhang, Xingdong Zhao.
United States Patent |
10,087,195 |
Wang , et al. |
October 2, 2018 |
Certain protein kinase inhibitors
Abstract
Provided are compound of formula (I) as certain CDK4/6
inhibitors, pharmaceutical compositions thereof, and methods of use
thereof. ##STR00001##
Inventors: |
Wang; Weibo (Moraga, CA),
Zhao; Xingdong (Moraga, CA), Li; Tongshuang (Surrey,
CA), Tian; Qiang (Chongqing, CN), Zhang;
Huajie (Chongqing, CN), Tan; Haohan (Chongqing,
CN), Wang; Xianlong (Chongqing, CN), Liu;
Qihong (Chongqing, CN), Li; Zhifu (Chongqing,
CN), Zhang; Weipeng (Chongqing, CN), Chen;
Zhifang (Chongqing, CN), Jiang; Lihua (Chongqing,
CN), Liu; Yanxin (Chongqing, CN), Linghu;
Li (Chongqing, CN), Lin; Min (Chongqing,
CN), Sun; Jing (Chongqing, CN) |
Applicant: |
Name |
City |
State |
Country |
Type |
Shanghai Fochon Pharmaceutical Co., Ltd.
CHONGQING FOCHON PHARMACEUTICAL CO., LTD. |
Shanghai
Chongqing |
N/A
N/A |
CN
CN |
|
|
Assignee: |
SHANGHAI FOCHON PHARMACEUTICAL CO.,
LTD. (Shanghai, CN)
CHONGQING FOCHON PHARMACEUTICAL CO., LTD. (Chongqing,
CN)
|
Family
ID: |
54698110 |
Appl.
No.: |
15/314,006 |
Filed: |
May 27, 2015 |
PCT
Filed: |
May 27, 2015 |
PCT No.: |
PCT/CN2015/079910 |
371(c)(1),(2),(4) Date: |
November 25, 2016 |
PCT
Pub. No.: |
WO2015/180642 |
PCT
Pub. Date: |
December 03, 2015 |
Prior Publication Data
|
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|
|
Document
Identifier |
Publication Date |
|
US 20170267696 A1 |
Sep 21, 2017 |
|
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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62003626 |
May 28, 2014 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
31/519 (20130101); C07D 519/00 (20130101); A61K
31/53 (20130101); A61P 29/00 (20180101); A61K
31/5377 (20130101); C07D 491/048 (20130101); C07D
403/12 (20130101); C07D 403/14 (20130101); A61P
35/00 (20180101); A61K 45/06 (20130101); C07D
495/04 (20130101); C07D 401/14 (20130101); C07D
487/04 (20130101); C07D 401/12 (20130101); A61P
43/00 (20180101); A61K 31/519 (20130101); A61K
2300/00 (20130101); A61K 31/5377 (20130101); A61K
2300/00 (20130101); A61K 31/53 (20130101); A61K
2300/00 (20130101) |
Current International
Class: |
C07D
487/04 (20060101); C07D 403/12 (20060101); C07D
403/14 (20060101); C07D 401/14 (20060101); C07D
401/12 (20060101); A61K 31/519 (20060101); C07D
519/00 (20060101); C07D 495/04 (20060101); A61K
31/53 (20060101); C07D 491/048 (20060101); A61K
31/5377 (20060101); A61P 35/00 (20060101) |
Field of
Search: |
;544/278 ;514/260.1 |
Other References
Cecil Textbook of Medicine, edited by Bennet, J.C., and Plum F.,
20th edition,vol. 1, 1004-101 O, 1996. cited by examiner .
Freshney et al.,Culture of Animal Cells, A Manual of Basic
Technique, Alan R. Liss, Inc., 1983, New York, p. 4. cited by
examiner .
Dermeret al., Bio/Technology, 1994, 12:320. cited by examiner .
Golub et al., Science, 286, 531-537, 1999. cited by examiner .
Cohen et al., Current Opinion in Chemical Biology, 3,459-465, 1999.
cited by examiner.
|
Primary Examiner: Balasubramanian; Venkataraman
Attorney, Agent or Firm: Pua; Meng H. Foley & Lardner
LLP
Parent Case Text
RELATED APPLICATIONS
This application is the U.S. National Stage of International Patent
Application Number PCT/CN2015/079910, filed May 27, 2015, which
claims priority to and the benefit of U.S. Provisional Patent
Application No. 62/003,626, filed May 28, 2014. The contents of the
foregoing are hereby incorporated herein by reference in their
entireties.
Claims
What is claimed is:
1. A compound of formula (I): ##STR00105## or a pharmaceutically
acceptable salt thereof, wherein: X is C; Y is S; 6-5 membered
fused ring system A-B is ##STR00106## Q is selected from aryl and
heteroaryl; R.sup.1 is selected from: hydrogen, C.sub.1-10 alkyl,
C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl,
heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl,
heteroaryl, and heteroaryl-C.sub.1-4 alkyl, wherein alkyl, alkenyl,
alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or
substituted with at least one substituent independently selected
from R.sup.6a, and wherein aryl and heteroaryl are each
unsubstituted or substituted with at least one substituent
independently selected from R.sup.6b; R.sup.2 is selected from:
hydrogen, halogen, hydroxyl, CN, C.sub.1-10 alkyl, C2-10 alkenyl,
C2-10 alkynyl, C.sub.3-10 cycloalkyl, C3-10 cycloalkyl-C.sub.14
alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl,
aryl-C.sub.1-4 alkyl, heteroaryl, and heteroaryl-C.sub.1-4 alkyl,
wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are
each unsubstituted or substituted with at least one substituent,
independently selected from R.sup.6a, and each aryl and heteroaryl
is unsubstituted or substituted with at least one substituent
independently selected from R.sup.6b; R.sup.3 and R.sup.4 are
independently selected from: hydrogen, C.sub.1-10 alkyl, C2-10
alkenyl, C2-10 alkynyl, and C3-10 cycloalkyl; wherein alkyl,
alkenyl, alkynyl, and cycloalkyl are each unsubstituted or
substituted with at least one substituent independently selected
from R.sup.6a; or R.sup.3 and R.sup.4 together with the nitrogen
atoms to which they are attached form a 4-12 membered ring
containing 0, 1, 2 or 3 heteroatoms independently selected from
oxygen, sulfur and nitrogen, and optionally substituted with for 1
or 2 R.sup.6a groups; with the proviso that when R.sup.3 and
R.sup.4 are both hydrogen, R.sup.2 is not aryl or heteroaryl; each
R.sup.5 is independently selected from: hydrogen, C.sub.1-10 alkyl,
C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl,
--OR.sup.8, --NR.sup.7S(O).sub.rR.sup.8, --NO.sub.2, -halogen,
--S(O).sub.rR.sup.7, --SR.sup.8, --S(O).sub.20R.sup.7,
--OS(O).sub.2R.sup.8, --S(O),NR.sup.7R.sup.8, --NR.sup.7R.sup.8,
--O(CR.sup.9R.sup.10).sub.tNR.sup.7R.sup.8, --C(O)R.sup.7,
--CO.sub.2R.sup.8,
--CO.sub.2(CR.sup.9R.sup.10).sub.tCONR.sup.7R.sup.8,
--OC(O)R.sup.7, --CN, --C(O)NR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8,
--OC(O)NR.sup.7R.sup.8, --NR.sup.7C(O)OR.sup.8,
--NR.sup.7C(O)NR.sup.7R.sup.8, --CR.sup.7(N-OR.sup.8), --CHF.sub.2,
--CF.sub.3, --OCHF.sub.2, and --OCF.sub.3; wherein C.sub.1-10
alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, and C.sub.3-10
cycloalkyl are each unsubstituted or substituted with at least one
substituent independently selected from R.sup.6a; each R.sup.6a is
independently selected from: -C.sub.1-10 alkyl, --C.sub.2-10
alkenyl, -C.sub.2-10 alkynyl, -C.sub.3-10 cycloalkyl, --OR.sup.8,
--NR.sup.7S(O).sub.rR.sup.8, --NO.sub.2, -halogen,
--S(O).sub.rR.sup.7, --SR.sub.8, --S(O).sub.2OR.sup.7,
--OS(O).sub.2R.sup.8, --S(O).sub.rNR.sup.7R.sup.8,
--NR.sup.7R.sup.8, --(CR.sup.9R.sup.10).sub.tOR.sup.8,
--(CR.sup.9R.sup.10).sub.tNR.sup.7R.sup.8,
--(CR.sup.9R.sup.10).sub.tSR.sup.8,
--(CR.sup.9R.sup.10).sub.tS(O).sub.r,R.sup.8,
--(CR.sup.9R.sup.10).sub.tCO.sub.2R.sup.8,
--(CR.sup.9R.sup.10).sub.tCONR.sup.7R.sup.8,
--(CR.sup.9R.sup.10).sub.tNR.sup.7CO.sub.2R.sup.8,
--(CR.sup.9R.sup.10).sub.tOCONR.sup.7R.sup.8,
--(CR.sup.9R.sup.10).sub.tNR.sup.7CONR.sup.7R.sup.8,
--(CR.sup.9R.sup.10).sub.tNR.sup.7SO.sub.2NR.sup.7R.sup.8,
--O(CR.sup.9R.sup.10).sub.tNR.sup.7R.sup.8, --C(O)R.sup.7,
--C(O)(CR.sup.9R.sup.10).sub.tOR.sup.8,
--C(O)(CR.sup.9R.sup.10).sub.tNR.sup.7R.sup.8,
--C(O)(CR.sup.9R.sup.10).sub.tSR.sup.8,
--C(O)(CR.sup.9R.sup.10).sub.tS(O).sub.rR.sup.8, --CO.sub.2R.sup.8,
--CO.sub.2(CR.sup.9R.sup.10).sub.tCONR.sup.7R.sup.8,
--OC(O)R.sup.7, --CN, --C(O)NR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8,
--OC(O)NR.sup.7R.sup.8, --NR.sup.7C(O)OR.sup.8,
--NR.sup.7C(O)NR.sup.7R.sup.8, --CR.sup.7(N--OR.sup.8),
--CHF.sub.2, --CF.sub.3, --OCHF.sub.2, and --OCF.sub.3; each
R.sup.6b is independently selected from: R.sup.6a, aryl,
aryl-C.sub.1-4 alkyl, heteroaryl, and heteroaryl-C.sub.1-4 alkyl;
each R.sup.7 and each R.sup.8 are independently selected from:
hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl,
cycloalkyl, cycloalkyl-C.sub.1-4 alkyl, heterocyclyl,
heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl,
heteroaryl, and heteroaryl-C.sub.1-4 alkyl; wherein alkyl, alkenyl,
alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or
substituted with at least one substituent, independently selected
from R.sup.6a, and aryl and heteroaryl are each unsubstituted or
substituted with at least one substituent independently selected
from R.sup.6b; or R.sup.7 and R.sup.8 together with the atom(s) to
which they are attached form a heterocyclic ring of 4 to 12 members
containing 0, 1, or 2 additional heteroatoms independently selected
from oxygen, sulfur and nitrogen, and optionally substituted with 1
or 2 R.sup.6b groups; each R.sup.9 and each R.sup.10 are
independently selected from: hydrogen, C.sub.1-10, C.sub.2-10
alkenyl, C.sub.2-10 alkynyl, cycloalkyl, cycloalkyl-C1-4 alkyl,
heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl,
heteroaryl, and heteroaryl-C.sub.1-4 alkyl; or R.sup.9 and R.sup.10
together with the carbon atom(s) to which they are attached form a
ring of 3 to 7 members containing 0, 1, or 2 heteroatoms
independently selected from oxygen, sulfur and nitrogen, and
optionally substituted with 1 or 2 R.sup.6a groups; m is
independently selected from 0, 1, 2, and 3; each r is independently
selected from 1 and 2; each t is independently selected from 1, 2,
and 3.
2. The compound of claim 1 or a pharmaceutically acceptable salt
thereof, wherein Q is selected from heteroaryl.
3. The compound of claim 2 or a pharmaceutically acceptable salt
thereof, wherein Q is selected from pyridyl, pyridazinyl and
5,6,7,8-tetrahydro-1,6-naphthyridinyl.
4. The compound of claim 3 or a pharmaceutically acceptable salt
thereof, wherein Q is selected from pyridin-2-yl, pyridazin-3-yl
and 5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl.
5. The compound of claim 1 or a pharmaceutically acceptable salt
thereof, wherein R.sup.1 is selected from hydrogen, C.sub.1-10
alkyl, heterocyclyl and heterocyclyl-C.sub.1-4 alkyl, wherein
heterocyclyl is unsubstituted or substituted with at least one
substituent independently selected from R.sup.6a, wherein each
R.sup.6a is independently selected from C.sub.1-10 alkyl,
--NR.sup.7R.sup.8, --(CR.sup.9R.sup.10).sub.tOR.sup.8, --OR.sup.8,
--C(O)R.sup.7, --(CR.sup.9R.sup.10).sub.tS(O).sub.rR.sup.8; wherein
R.sup.7, R.sup.8, R.sup.9, R.sup.10, t and r are described as in
claim 1.
6. The compound of claim 5 or a pharmaceutically acceptable salt
thereof, wherein Q is selected from pyridin-2-yl, pyridazin-3-yl,
and R.sup.1 is selected from heterocyclyl and
heterocyclyl-C.sub.1-4alkyl groups consisting of the following
groups: ##STR00107## each heterocyclyl is unsubstituted or
substituted with at least one independently selected from R.sup.6a,
wherein each R.sup.6a is independently selected from C.sub.1-10
alkyl, --NR.sup.7R.sup.8, --(CR.sup.9R.sup.10).sub.tOR.sup.8,
--OR.sup.8, --C(O)R.sup.7, --C(O)NR.sup.7R.sup.8,
--(CR.sup.9R.sup.10).sub.tS(O).sub.rR.sup.8; wherein R.sup.7,
R.sup.8, R.sup.9, R.sup.10, t and r are described as in claim
1.
7. A compound of claim 5 or a pharmaceutically acceptable salt
thereof, wherein R.sup.6a is independently selected from hydrogen,
methyl, ethyl, hydroxyl, hydroxymethyl, hydroxyethyl,
hydroxyacetyl, methoxymethyl, methoxyethyl, acetyl, hydroxyacetyl,
(methyl sulfonyl)ethyl, amino, carbamoyl, methylamino, and
dimethylamino.
8. The compound claim 1 or a pharmaceutically acceptable salt
thereof, wherein R.sup.2 is selected from C.sub.3-10 cycloalkyl,
wherein cycloalkyl is unsubstituted or substituted with at least
one substituent independently selected from R.sup.6a, R.sup.6a is
described as in claim 1.
9. The compound of claim 8 or a pharmaceutically acceptable salt
thereof, wherein R.sup.2 is selected from cyclopentyl and
cyclohexyl, wherein cyclohexyl is unsubstituted or substituted with
methyl.
10. The compound claim 1 or a pharmaceutically acceptable salt
thereof, wherein R.sup.3 and R.sup.4 are independently selected
from hydrogen, C.sub.1-10 alkyl and cyclopropyl.
11. The compound claim 1 or a pharmaceutically acceptable salt
thereof, wherein R.sup.3 and R.sup.4 together with the nitrogen
atoms to which they are attached form azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl, and morpholino, wherein the formed ring
is unsubstituted or substituted with methyl, hydroxyl, and
methoxy.
12. The compound claim 1 or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is independently selected from hydrogen,
C.sub.1-10 alkyl and --C(O)R.sup.7, wherein R.sup.7 is selected
from methyl and hydroxymethyl.
13. The compound of claim 1, selected from
7-cyclopentyl-N,N-dimethyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)thieno[-
3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino-
)thieno[3,2-d]pyrimidine-6-carboxamide,
(S)-7-cyclopentyl-N,N-dimethyl-2((5-(3-oxotetrahydro-3H-oxazolo[3,4-a]pyr-
azin-7(1H)-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
(R)-7-cyclopentyl-N,N-dimethyl-2-((5-(3-oxotetrahydro-3H-oxazolo[3,4-a]py-
razin-7(1H)-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
(R)-7-cyclopentyl-N,N-dimethyl-2-((5-(morpholin-2-yl)pyridin-2-yl)amino)t-
hieno[3,2-d]pyrimidine-6-carboxamide,
2-((5-(4-aminopiperidin-1-yl)pyridin-2-yl)amino)-7-cyclopentyl-N,N-dimeth-
ylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(4-(methylamino)piperidin-1-yl)pyridin-2-
-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-2-((5-(4-(dimethylamino)piperidin-1-yl)pyridin-2-yl)amino)--
N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(S)-7-cyclopentyl-2-((5-(3-(methoxymethyl)piperazin-1-yl)pyridin-2-yl)ami-
no)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(S)-7-cyclopentyl-2-((5-(3-(methoxymethyl)-4-methylpiperazin-1-yl)pyridin-
-2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(S)-7-cyclopentyl-2-((5-(4-ethyl-3-(methoxymethyl)piperazin-1-yl)pyridin--
2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(S)-7-cyclopentyl-2-((5-(3-(hydroxymethyl)piperazin-1-yl)pyridin-2-yl)ami-
no)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(S)-7-cyclopentyl-2-((5-(3-(hydroxymethyl)-4-methylpiperazin-1-yl)pyridin-
-2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(S)-7-cyclopentyl-2-((5-(4-ethyl-3-(hydroxymethyl)piperazin-1-yl)pyridin--
2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(R)-7-cyclopentyl-2-((5-(3-(methoxymethyl)piperazin-1-yl)pyridin-2-yl)ami-
no)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(R)-7-cyclopentyl-2-((5-(3-(methoxymethyl)-4-methylpiperazin-1-yl)pyridin-
-2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(R)-7-cyclopentyl-2-((5-(4-ethyl-3-(methoxymethyl)piperazin-1-yl)pyridin--
2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(R)-7-cyclopentyl-2-((5-(3-(hydroxymethyl)piperazin-1-yl)pyridin-2-yl)ami-
no)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(R)-7-cyclopentyl-2-((5-(3-(hydroxymethyl)-4-methylpiperazin-1-yl)pyridin-
-2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(R)-7-cyclopentyl-2-((5-(4-ethyl-3-(hydroxymethyl)piperazin-1-yl)pyridin--
2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)thien-
o[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)ami-
no)thieno[3,2-d]pyrimidine-6-carboxamide,
2-((5-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)amino)-7-cyclop-
entyl-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-ylmethyl)pyridin-2-yl)amino-
)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-((4-methylpiperazin-1-yl)methyl)pyridin--
2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-N,-
N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
2-((5-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)amino)-7-c-
yclopentyl-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1-
]heptan-2-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
(R)-7-cyclopentyl-2-((5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin--
2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(S)-7-cyclopentyl-2-((5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin--
2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
2-((5-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)amino)-7-c-
yclopentyl-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
2-((5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-2-yl)amino)-7-cyclopent-
yl-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(6-methyl-3,6-diazabicyclo[3.1.1]heptan--
3-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-2-((5-(6-ethyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-2-
-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-2-((5-((7R,8aR)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1-
H)-yl)pyridin-2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamid-
e,
7-cyclopentyl-2-((5-((7S,8aR)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2-
(1H)-yl)pyridin-2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxam-
ide,
7-cyclopentyl-2-((5-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-
-2(1H)-yl)pyridin-2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carbox-
amide,
2-((5-(3,6-diazabicyclo[3.2.0]heptan-3-yl)pyridin-2-yl)amino)-7-cyc-
lopentyl-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(6-methyl-3,6-diazabicyclo[3.2.0]heptan--
3-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-2-((5-(6-ethyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)pyridin-2-
-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((6-(piperazin-1-yl)pyridazin-3-yl)amino)thi-
eno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((6-(4-methylpiperazin-1-yl)pyridazin-3-yl)a-
mino)thieno[3,2-d]pyrimidine-6-carboxamide,
2-((6-(4-acetylpiperazin-1-yl)pyridazin-3-yl)amino)-7-cyclopentyl-N,N-dim-
ethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-2-((6-(4-(2-hydroxyacetyl)piperazin-1-yl)pyridazin-3-yl)ami-
no)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((6-(4-(2-(methylsulfonyl)ethyl)piperazin-1--
yl)pyridazin-3-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)a-
mino)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((6-methyl-5,6,7,8-tetrahydro-1,6-naphthyrid-
in-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-2-((5-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-2-yl)amino)-
-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-2-((5-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-2-yl)amino)-
-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(4-(2-(methylsulfonyl)ethyl)piperazin-1--
yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-2-((5-(4-ethylpiperazin-1-yl)pyridin-2-yl)amino)-N,N-dimeth-
ylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-2-((5-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)amin-
o)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide
7-cyclopentyl-N,N-dimethyl-2-((5-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)p-
yridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide
7-cyclopentyl-2-((5-((3S,5R)-4-ethyl-3,5-dimethylpiperazin-1-yl)pyridin-2-
-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide
7-cyclopentyl-N,N-dimethyl-2-((5-(1-methyl-2,4-dioxo-1,3,8-triazaspiro[4.-
5]decan-8-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide
2-((5-(4-carbamoyl-4-(methylamino)piperidin-1-yl)pyridin-2-yl)amino)-7-cy-
clopentyl-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide
azetidin-1-yl(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thie-
no[3,2-d]pyrimidin-6-yl)methanone,
(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyri-
midin-6-yl)(3-methoxyazetidin-1-yl)methanone,
(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyri-
midin-6-yl)(3-hydroxyazetidin-1-yl)methanone,
(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyri-
midin-6-yl)(piperidin-1-yl)methanone,
(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyri-
midin-6-yl)(4-methylpiperazin-1-yl)methanone,
(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyri-
midin-6-yl)(piperazin-1-yl)methanone,
7-cyclopentyl-N-cyclopropyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thie-
no[3,2-d]pyrimidine-6-carboxamide,
(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyri-
midin-6-yl)(pyrrolidin-1-yl)methanone,
7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrim-
idine-6-carboxamide,
7-cyclopentyl-N-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,-
2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N-ethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-
-d]pyrimidine-6-carboxamide,
(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyri-
midin-6-yl)(morpholino)methanone,
azetidin-1-yl(7-cyclopentyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)am-
ino)thieno[3,2-d]pyrimidin-6-yl)methanone,
(7-cyclopentyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)thieno[3,-
2-d]pyrimidin-6-yl)(3-methoxyazetidin-1-yl)methanone,
(7-cyclopentyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)thieno[3,-
2-d]pyrimidin-6-yl)(piperidin-1-yl)methanone,
(7-cyclopentyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)thieno[3,-
2-d]pyrimidin-6-yl)(4-methylpiperazin-1-yl)methanone,
7-cyclopentyl-N-cyclopropyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)am-
ino)thieno[3,2-d]pyrimidine-6-carboxamide,
(7-cyclopentyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)thieno[3,-
2-d]pyrimidin-6-yl)(pyrrolidin-1-yl)methanone,
7-cyclopentyl-N-methyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)t-
hieno[3,2-d]pyrimidine-6-carboxamide,
(7-cyclopentyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)thieno[3,-
2-d]pyrimidin-6-yl)(morpholino)methanone,
N,N-dimethyl-7-((1r,4r)-4-methylcyclohexyl)-2-((5-(piperazin-1-yl)pyridin-
-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
N,N-dimethyl-7-((1r,4r)-4-methylcyclohexyl)-2-((5-(4-methylpiperazin-1-yl-
)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
N,N-dimethyl-7-((1r,4r)-4-methylcyclohexyl)-2-((5,6,7,8-tetrahydro-1,6-na-
phthyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
N,N-dimethyl-2-((6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino)-
-7-((1r,4r)-4-methylcyclohexyl)thieno[3,2-d]pyrimidine-6-carboxamide,
2-((6-acetyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino)-N,N-dimethyl-
-7-((1r,4r)-4-methylcyclohexyl)thieno[3,2-d]pyrimidine-6-carboxamide,
2-((6-(2-hydroxyacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino)-N-
,N-dimethyl-7-((1r,4r)-4-methylcyclohexyl)thieno[3,2-d]pyrimidine-6-carbox-
amide,
N,N-dimethyl-7-((1r,4r)-4-methylcyclohexyl)-2-((6-(piperazin-1-yl)p-
yridazin-3-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
N,N-dimethyl-7-((1r,4r)-4-methylcyclohexyl)-2-((6-(4-methylpiperazin-1-yl-
)pyridazin-3-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
2-((6-(4-acetylpiperazin-1-yl)pyridazin-3-yl)amino)-N,N-dimethyl-7-((1r,4-
r)-4-methylcyclohexyl)thieno[3,2-d]pyrimidine-6-carboxamide,
2-((6-(4-(2-hydroxyacetyl)piperazin-1-yl)pyridazin-3-yl)amino)-N,N-dimeth-
yl-7-((1r,4r)-4-methylcyclohexyl)thieno[3,2-d]pyrimidine-6-carboxamide,
or pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound of claim 1
or a pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable carrier.
Description
FIELD OF THE INVENTION
Provided are certain compounds and/or pharmaceutically acceptable
salts thereof which can inhibit kinase activity of CDK4/6 and may
be useful for the treatment of hyper-proliferative diseases like
cancer and inflammation.
BACKGROUND OF THE INVENTION
Hyper-proliferative diseases like cancer and inflammation are
attracting the scientific community to provide therapeutic
benefits. In this regard efforts have been made to identify and
target specific mechanisms which play a role in proliferating the
diseases.
Tumor development is closely associated with genetic alteration and
deregulation of cyclin-dependent kinases (CDKs) and their
regulators, suggesting that inhibitors of CDKs may be useful
anti-cancer therapeutics.
CDKs are serine/threonine protein kinases, which are the driving
force behind the cell cycle and cell proliferation. CDKs regulate
initiation, progression, and completion of mammalian cell cycle,
and they are critical for cell growth. Most of the known CDK's,
including CDK1 through CDK9, are involved either directly or
indirectly in cell cycle progression. Those directly involved with
cell cycle progression, such as CDK1-4 and 6, can be classified as
G1, S, or G2M phase enzymes. Uncontrolled proliferation is a
hallmark of cancer cells and the alteration of CDK function occurs
with high frequency in many solid tumors.
The pivotal roles of CDKs, and their associated proteins, in
coordinating and driving the cell cycle in proliferating cells have
been outlined. The development of monotherapies for the treatment
of proliferative disorders, such as cancers, using therapeutics
targeted generically at CDKs, or at specific CDKs, is therefore
potentially highly desirable. CDK inhibitors could conceivably also
be used to treat other conditions such as viral infections,
autoimmune diseases and neuro-degenerative diseases, amongst
others. CDKs targeted therapeutics may also provide clinical
benefits in the treatment of the previously described diseases when
used in combination therapy with either existing, or new,
therapeutic agents.
Therefore, a compound having an inhibitory activity on CDK will be
useful for the prevention or treatment of cancer. Although CDK4/6
inhibitors were disclosed in the arts, e.g., WO2010020675 and
WO2012064805, many suffer from having short half-life or toxicity.
Therefore, there is a need for new CDK4/6 inhibitors that have at
least one advantageous property selected from potency, stability,
selectivity, toxicity and pharmacodynamics properties as an
alternative for the treatment of hyper-proliferative diseases. In
this regard, a novel class of CDK4/6 inhibitors is provided
herein.
DISCLOSURE OF THE INVENTION
Disclosed herein are certain novel 6-5 membered fused ring
derivatives and pharmaceutical compositions thereof, and their use
as pharmaceuticals.
In one aspect, disclosed herein is at least one compound of formula
(I):
##STR00002##
and/or at least one pharmaceutically acceptable salt thereof,
wherein:
X is C or N;
Y is CR.sup.11, O, S, or NR.sup.12;
6-5 membered fused ring system A-B is selected from:
##STR00003##
Q is selected from aryl and heteroaryl;
R.sup.1 is selected from: hydrogen, C.sub.1-10 alkyl, C.sub.2-10
alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4
alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, and
heteroaryl-C.sub.1-4alkyl, wherein alkyl, alkenyl, alkynyl,
cycloalkyl, and heterocyclyl are each unsubstituted or substituted
with at least one substituent, such as one, two, three, or four
substituents, independently selected from R.sup.6a, and wherein
aryl and heteroaryl are each unsubstituted or substituted with at
least one substituent, such as one, two, three, or four
substituents, independently selected from R.sup.6b;
R.sup.2 is selected from: hydrogen, halogen, hydroxyl, CN,
C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl,
C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl,
heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.14
alkyl, heteroaryl, and heteroaryl-C.sub.1-4 alkyl, wherein alkyl,
alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each
unsubstituted or substituted with at least one substituent, such as
one, two, three, or four substituents, independently selected from
R.sup.6a, and each aryl and heteroaryl is unsubstituted or
substituted with at least one substituent, such as one, two, three,
or four substituents, independently selected from R.sup.6b;
R.sup.3 and R.sup.4 are independently selected from: hydrogen,
C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, and
C.sub.3-10 cycloalkyl; wherein alkyl, alkenyl, alkynyl, and
cycloalkyl are each unsubstituted or substituted with at least one
substituent, such as one, two, three, or four substituents,
independently selected from R.sup.6a; or R.sup.3 and R.sup.4
together with the nitrogen atoms to which they are attached form a
4-12 membered ring containing, 1, 2 or 3 heteroatoms independently
selected from oxygen, sulfur and nitrogen, and optionally
substituted with 1 or 2 R.sup.6a groups;
with the proviso that when R.sup.3 and R.sup.4 are both hydrogen,
R.sup.2 is not aryl or heteroaryl;
each R.sup.5 is independently selected from: hydrogen, C.sub.1-10
alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10
cycloalkyl, --OR.sup.8, --NR.sup.7S(O).sub.rR.sup.8, --NO.sub.2,
halogen, --S(O).sub.rR.sup.7, --SR.sup.8, --S(O).sub.2OR.sup.7,
--OS(O).sub.2R.sup.8, --S(O).sub.rNR.sup.7R.sup.8,
--NR.sup.7R.sup.8, --O(CR.sup.9R.sup.10).sub.tNR.sup.7R.sup.8,
--C(O)R.sup.7, --CO.sub.2R.sup.8,
--CO.sub.2(CR.sup.9R.sup.10).sub.tCONR.sup.7R.sup.8,
--OC(O)R.sup.7, --CN, --C(O)NR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8,
--OC(O)NR.sup.7R.sup.8, --NR.sup.7C(O)OR.sup.8,
--NR.sup.7C(O)NR.sup.7R.sup.8, --CR.sup.7(N--OR.sup.8),
--CHF.sub.2, --CF.sub.3, --OCHF.sub.2, and --OCF.sub.3; wherein
C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, and
C.sub.3-10 cycloalkyl are each unsubstituted or substituted with at
least one substituent, such as one, two, three, or four
substituents, independently selected from R.sup.6a;
each R.sup.6a is independently selected from: --C.sub.1-10 alkyl,
--C.sub.2-10 alkenyl, --C.sub.2-10 alkynyl, --C.sub.3-10
cycloalkyl, --OR.sup.8, --NR.sup.7S(O).sub.rR.sup.8, --NO.sub.2,
-halogen, --S(O).sub.rR.sup.7, --SR.sup.8, --S(O).sub.2OR.sup.7,
--OS(O).sub.2R.sup.8, --S(O).sub.rNR.sup.7R.sup.8,
--NR.sup.7R.sup.8, --(CR.sup.9R.sup.10).sub.tOR.sup.8,
--(CR.sup.9R.sup.10).sub.tNR.sup.7R.sup.8,
--(CR.sup.9R.sup.10).sub.tSR.sup.8,
--(CR.sup.9R.sup.10).sub.tS(O).sub.rR.sup.8,
--(CR.sup.9R.sup.10).sub.tCO.sub.2R.sup.8,
--(CR.sup.9R.sup.10).sub.tCONR.sup.7R.sup.8,
--(CR.sup.9R.sup.10).sub.tNR.sup.7CO.sub.2R.sup.8,
--(CR.sup.9R.sup.10).sub.tOCONR.sup.7R.sup.8,
--(CR.sup.9R.sup.10).sub.tNR.sup.7CONR.sup.7R.sup.8,
--(CR.sup.9R.sup.10).sub.tNR.sup.7SO.sub.2NR.sup.7R.sup.8,
--O(CR.sup.9R.sup.10).sub.tNR.sup.7R.sup.8, --C(O)R.sup.7,
--C(O)(CR.sup.9R.sup.10).sub.tOR.sup.8,
--C(O)(CR.sup.9R.sup.10).sub.tNR.sup.7R.sup.8,
--C(O)(CR.sup.9R.sup.10).sub.tSR.sup.8,
--C(O)(CR.sup.9R.sup.10).sub.tS(O).sub.rR.sup.8, --CO.sub.2R.sup.8,
--CO.sub.2(CR.sup.9R.sup.10).sub.tCONR.sup.7R.sup.8,
--OC(O)R.sup.7, --CN, --C(O)NR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8,
--OC(O)NR.sup.7R.sup.8, --NR.sup.7C(O)OR.sup.8,
--NR.sup.7C(O)NR.sup.7R.sup.8, --CR.sup.7(N--OR.sup.8),
--CHF.sub.2, --CF.sub.3, --OCHF.sub.2, and --OCF.sub.3;
each R.sup.6b is independently selected from: R.sup.6a, aryl,
aryl-C.sub.1-4 alkyl, heteroaryl, and heteroaryl-C.sub.1-4
alkyl;
each R.sup.7 and each R.sup.8 are independently selected from:
hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl,
cycloalkyl, cycloalkyl-C.sub.1-4 alkyl, heterocyclyl,
heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl,
heteroaryl, and heteroaryl-C.sub.1-4 alkyl; wherein alkyl, alkenyl,
alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or
substituted with at least one substituent, such as one, two, three,
or four substituents, independently selected from R.sup.6a, and
aryl and heteroaryl are each unsubstituted or substituted with at
least one substituent, such as one, two, three, or four
substituents, independently selected from R.sup.6b; or R.sup.7 and
R.sup.8 together with the atom(s) to which they are attached form a
heterocyclic ring of 4 to 12 members containing 0, 1, or 2
additional heteroatoms independently selected from oxygen, sulfur
and nitrogen, and optionally substituted with 1 or 2 R.sup.6b
groups;
each R.sup.9 and each R.sup.10 are independently selected from:
hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl,
cycloalkyl, cycloalkyl-C.sub.1-4 alkyl, heterocyclyl,
heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl,
heteroaryl, and heteroaryl-C.sub.1-4 alkyl; or R.sup.9 and R.sup.10
together with the carbon atom(s) to which they are attached form a
ring of 3 to 7 members containing 0, 1, or 2 heteroatoms
independently selected from oxygen, sulfur and nitrogen, and
optionally substituted with 1 or 2 R.sup.6a groups;
R.sup.11 is selected from: hydrogen, C.sub.1-10 alkyl, C.sub.3-10
cycloalkyl, C.sub.3-10 cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl,
heteroaryl-C.sub.1-4 alkyl, --OR.sup.7,
--NR.sup.7S(O).sub.rR.sup.8, --S(O).sub.rR.sup.7, --SR.sup.7,
--S(O).sub.2OR.sup.7, --OS(O).sub.2R.sup.7,
--S(O).sub.rNR.sup.7R.sup.8, --NR.sup.7R.sup.8,
--O(CR.sup.9R.sup.10).sub.tNR.sup.7R.sup.8, --C(O)R.sup.7,
--CO.sub.2R.sup.8,
--CO.sub.2(CR.sup.9R.sup.10).sub.tCONR.sup.7R.sup.8,
--OC(O)R.sup.7, --CN, --C(O)NR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8,
--OC(O)NR.sup.7R.sup.8, --NR.sup.7C(O)OR.sup.8,
--NR.sup.7C(O)NR.sup.7R.sup.8, --CHF.sub.2, --CF.sub.3,
--OCHF.sub.2, and --OCF.sub.3;
R.sup.12 is selected from: hydrogen, C.sub.1-10 alkyl, C.sub.3-10
cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl,
heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl,
heteroaryl, heteroaryl-C.sub.1-4 alkyl, --S(O).sub.rR.sup.7,
--C(O)R.sup.7, --CO.sub.2R.sup.7,
--CO.sub.2(CR.sup.9R.sup.10).sub.tCONR.sup.7R.sup.8, and
--C(O)NR.sup.7R.sup.8;
m is independently selected from 0, 1, 2, and 3;
each r is independently selected from 1 and 2;
each t is independently selected from 1, 2, and 3.
In yet another aspect, the present disclosure provides
pharmaceutical compositions comprising at least one compound of
formula (I) and/or at least one pharmaceutically acceptable salt
thereof and a pharmaceutically acceptable excipient.
In yet another aspect, the disclosure provides methods for
modulating CDK4/6, comprising administering to a system or a
subject in need thereof, a therapeutically effective amount of at
least one compound of formula (I) and/or at least one
pharmaceutically acceptable salt thereof or pharmaceutical
compositions thereof, thereby modulating said CDK4/6. The
disclosure also provides methods to treat, ameliorate or prevent a
condition which responds to inhibition of CDK4/6 comprising
administering to a system or subject in need of such treatment an
effective amount of at least one compound of formula (I) and/or at
least one pharmaceutically acceptable salt thereof or
pharmaceutical compositions thereof, and optionally in combination
with a second therapeutic agent, thereby treating said condition.
Alternatively, the present disclosure provides the use of at least
one compound of formula (I) and/or at least one pharmaceutically
acceptable salt thereof in the manufacture of a medicament for
treating a condition mediated by CDK4/6. In particular embodiments,
the compounds of the disclosure may be used alone or in combination
with a second therapeutic agent to treat a condition mediated by
CDK4/6, wherein said condition is an autoimmune disease, a
transplantation disease, an infectious disease or a cell
proliferative disorder.
Furthermore, the disclosure provides methods for treating a cell
proliferative disorder, comprising administering to a system or
subject in need of such treatment an effective amount of at least
one compound of formula (I) and/or at least one pharmaceutically
acceptable salt thereof or pharmaceutical compositions thereof, and
optionally in combination with a second therapeutic agent, thereby
treating said condition.
Alternatively, the present disclosure provides the use of at least
one compound of formula (I) and/or at least one pharmaceutically
acceptable salt thereof in the manufacture of a medicament for
treating a cell-proliferative disorder. In particular examples, the
compounds of the disclosure may be used alone or in combination
with a chemotherapeutic agent to treat a cell proliferative
disorder, including but not limited to, lymphoma, osteosarcoma,
melanoma, or a tumor of breast, renal, prostate, colorectal,
thyroid, ovarian, pancreatic, neuronal, lung, uterine or
gastrointestinal tumor.
In the above methods for using the compounds of the disclosure, at
least one compound of formula (I) and/or at least one
pharmaceutically acceptable salt thereof may be administered to a
system comprising cells or tissues, or to a mammalian subject such
as a human or animal subject.
DETAILED DESCRIPTION OF THE INVENTION
As used herein the following definitions are applicable.
The term "alkyl" refers to both branched and straight-chain
saturated aliphatic hydrocarbon groups having the specified number
of carbon atoms. Unless otherwise specified, "alkyl" refers to
C.sub.1-C.sub.6 alkyl. For example, C.sub.1-C.sub.6, as in
"C.sub.1-6 alkyl" is defined to include groups having 1, 2, 3, 4,
5, or 6 carbons in a linear or branched arrangement. For example,
"C.sub.1-8 alkyl" includes but is not limited to methyl, ethyl,
n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl,
heptyl, and octyl.
The term "cycloalkyl" means a saturated aliphatic cyclic
hydrocarbon group having the specified number of carbon atoms.
Unless otherwise specified, "cycloalkyl" refers to C.sub.3-10
cycloalkyl. For example, "cycloalkyl" includes but is not limited
to cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl,
cyclopentyl, 2-ethyl-cyclopentyl, cyclohexyl, and
trans-4-methylcyclohexyl.
The term "alkenyl" refers to a non-aromatic hydrocarbon radical,
straight, branched or cyclic, containing from 2 to 10 carbon atoms
and at least one carbon to carbon double bond. In some embodiments,
one carbon to carbon double bond is present, and up to four
non-aromatic carbon-carbon double bonds may be present. Thus,
"C.sub.2-6 alkenyl" means an alkenyl radical having from 2 to 6
carbon atoms. Alkenyl groups include but are not limited to
ethenyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The
straight, branched or cyclic portion of the alkenyl group may
contain double bonds and may be substituted if a substituted
alkenyl group is indicated.
The term "alkynyl" refers to a hydrocarbon radical straight,
branched or cyclic, containing from 2 to 10 carbon atoms and at
least one carbon to carbon triple bond. In some embodiments, up to
three carbon-carbon triple bonds may be present. Thus, "C.sub.2-6
alkynyl" means an alkynyl radical having from 2 to 6 carbon atoms.
Alkynyl groups include but are not limited to ethynyl, propynyl,
butynyl, and 3-methylbutynyl. The straight, branched or cyclic
portion of the alkynyl group may contain triple bonds and may be
substituted if a substituted alkynyl group is indicated.
The term "aryl" encompasses: 5- and 6-membered carbocyclic aromatic
rings, for example, benzene; bicyclic ring systems wherein at least
one ring is carbocyclic and aromatic, for example, naphthalene,
indane, and 1, 2, 3, 4-tetrahydroquinoline; and tricyclic ring
systems wherein at least one ring is carbocyclic and aromatic, for
example, fluorene. In cases where the aryl substituent is bicyclic
or tricyclic and at least one ring is non-aromatic, it is
understood that attachment is via the aromatic ring.
For example, aryl includes 5- and 6-membered carbocyclic aromatic
rings fused to a 5- to 7-membered heterocyclic ring containing one
or more heteroatoms selected from N, O, and S, provided that the
point of attachment is at the carbocyclic aromatic ring. Bivalent
radicals formed from substituted benzene derivatives and having the
free valences at ring atoms are named as substituted phenylene
radicals. Bivalent radicals derived from univalent polycyclic
hydrocarbon radicals whose names end in "-yl" by removal of one
hydrogen atom from the carbon atom with the free valence are named
by adding "-idene" to the name of the corresponding univalent
radical, e.g., a naphthyl group with two points of attachment is
termed naphthylidene. Aryl, however, does not encompass or overlap
in any way with heteroaryl, separately defined below. Hence, if one
or more carbocyclic aromatic rings are fused with a heterocyclic
aromatic ring, the resulting ring system is heteroaryl, not aryl,
as defined herein.
The term "halogen" (or "halo") refers to fluorine, chlorine,
bromine and iodine.
The term "heteroaryl" refers to
5- to 8-membered aromatic, monocyclic rings containing one or more,
for example, from 1 to 4, or, in some embodiments, from 1 to 3,
heteroatoms selected from N, O, and S, with the remaining ring
atoms being carbon;
8- to 12-membered bicyclic rings containing one or more, for
example, from 1 to 4, or, in some embodiments, from 1 to 3,
heteroatoms selected from N, O, and S, with the remaining ring
atoms being carbon and wherein at least one heteroatom is present
in an aromatic ring; and
11- to 14-membered tricyclic rings containing one or more, for
example, from 1 to 4, or in some embodiments, from 1 to 3,
heteroatoms selected from N, O, and S, with the remaining ring
atoms being carbon and wherein at least one heteroatom is present
in an aromatic ring.
When the total number of S and O atoms in the heteroaryl group
exceeds 1, those heteroatoms are not adjacent to one another. In
some embodiments, the total number of S and O atoms in the
heteroaryl group is not more than 2. In some embodiments, the total
number of S and O atoms in the aromatic heterocycle is not more
than 1.
Examples of heteroaryl groups include, but are not limited to, (as
numbered from the linkage position assigned priority 1), 2-pyridyl,
3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl,
2,4-pyrimidinyl, 3,5-pyrimidinyl, 1-pyrazolyl, 2,3-pyrazolyl,
2,4-imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl,
tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl,
benzoimidazolinyl, indolinyl, pyridizinyl, triazolyl, quinolinyl,
pyrazolyl, and 5,6,7,8-tetrahydroisoquinoline.
Further heteroaryl groups include but are not limited to pyrrolyl,
isothiazolyl, triazinyl, pyrazinyl, pyridazinyl, indolyl,
benzotriazolyl, quinoxalinyl, and isoquinolinyl. As with the
definition of heterocycle below, "heteroaryl" is also understood to
include the N-oxide derivative of any nitrogen-containing
heteroaryl.
Bivalent radicals derived from univalent heteroaryl radicals whose
names end in "-yl" by removal of one hydrogen atom from the atom
with the free valence are named by adding "-idene" to the name of
the corresponding univalent radical, e.g., a pyridyl group with two
points of attachment is a pyridylidene. Heteroaryl does not
encompass or overlap with aryl as defined above.
In cases where the heteroaryl substituent is bicyclic or tricyclic
and at least one ring is non-aromatic or contains no heteroatoms,
it is understood that attachment is via the aromatic ring or via
the heteroatom containing ring, respectively.
The term "heterocycle" (and variations thereof such as
"heterocyclic", or "heterocyclyl") broadly refers to a single
aliphatic ring, usually with 3 to 12 ring atoms, containing at
least 2 carbon atoms in addition to one or more, preferably one to
three heteroatoms independently selected from oxygen, sulfur, and
nitrogen, as well as combinations comprising at least one of the
foregoing heteroatoms. Alternatively, a heterocycle as defined
above may be multicyclic ring system (e.g. bicyclic) in which two
or more rings may be fused or bridged or spiro together, wherein at
least one such ring contains one or more heteroatoms independently
selected from oxygen, sulfur, and nitrogen. "Heterocycle" also
refers to 5- to 7-membered heterocyclic ring containing one or more
heteroatoms selected from N, O, and S fused with 5- and 6-membered
carbocyclic aromatic ring, provided that the point of attachment is
at the heterocyclic ring. The rings may be saturated or have one or
more double bonds (i.e. partially unsaturated). The heterocycle can
be substituted by oxo. The point of the attachment may be carbon or
heteroatom in the heterocyclic ring, provided that attachment
results in the creation of a stable structure. When the
heterocyclic ring has substituents, it is understood that the
substituents may be attached to any atom in the ring, whether a
heteroatom or a carbon atom, provided that a stable chemical
structure results. Heterocycle does not overlap with
heteroaryl.
Suitable heterocycles include, for example (as numbered from the
linkage position assigned priority 1), 1-pyrrolidinyl,
2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl,
1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,
2,5-piperazinyl. 1,4-piperazinyl, and 2,3-pyridazinyl. Morpholinyl
groups are also contemplated, including 2-morpholinyl and
3-morpholinyl (numbered wherein the oxygen is assigned priority 1).
Substituted heterocycle also includes ring systems substituted with
one or more oxo moieties, such as piperidinyl N-oxide,
morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and
1,1-dioxo-1-thiomorpholinyl. Bicyclic heterocycles include, for
example:
##STR00004## ##STR00005##
As used herein, "arylalkyl" refers to an alkyl moiety substituted
by an aryl group. Example arylalkyl groups include benzyl,
phenethyl, and naphthylmethyl groups. In some embodiments,
arylalkyl groups have from 7 to 20 or 7 to 11 carbon atoms. When
used in the phrase "arylC.sub.1-4 alkyl", the term "C.sub.1-4"
refers to the alkyl portion of the moiety and does not describe the
number of atoms in the aryl portion of the moiety. Likewise, when
used in the phrase "arylC1-.sub.10 alkyl", the term "C.sub.1-10"
refers to the alkyl portion of the moiety and does not describe the
number of atoms in the aryl portion of the moiety.
As used herein, "heterocyclylalkyl" refers to alkyl substituted by
heterocyclyl. When used in the phrase "heterocyclyl-C.sub.1-6
alkyl", the term "C.sub.1-6" refers to the alkyl portion of the
moiety and does not describe the number of atoms in the
heterocyclyl portion of the moiety.
As used herein, "cycloalkylalkyl" refers to alkyl substituted by
cycloalkyl. When used in the phrase "C.sub.3-10 cycloalkylalkyl",
the term "C.sub.3-10" refers to the cycloalkyl portion of the
moiety and does not describe the number of atoms in the alkyl
portion of the moiety. When used in the phrase "C.sub.3-7
cycloalkylalkyl", the term "C.sub.3-7" refers to the cycloalkyl
portion of the moiety and does not describe the number of atoms in
the alkyl portion of the moiety. When used in the phrase "C.sub.3-8
cycloalkylalkyl", the term "C.sub.3-8" refers to the cycloalkyl
portion of the moiety and does not describe the number of atoms in
the alkyl portion of the moiety. When used in the phrase
"cycloalkyl C.sub.1-10 alkyl", the term "C.sub.1-10" refers to the
alkyl portion of the moiety and does not describe the number of
atoms in the cycloalkyl portion of the moiety.
As used herein, "heteroarylalkyl" refers to alkyl substituted by
heteroaryl. When used in the phrase "heteroaryl C.sub.1-4 alkyl",
the term "C.sub.1-4" refers to the alkyl portion of the moiety and
does not describe the number of atoms in the heteroaryl portion of
the moiety. Likewise, when used in the phrase "heteroaryl
C.sub.1-10 alkyl", the term "C.sub.1-10" refers to the alkyl
portion of the moiety and does not describe the number of atoms in
the heteroaryl portion of the moiety.
For avoidance of doubt, reference, for example, to substitution of
alkyl, cycloalkyl, heterocyclyl, aryl, and/or heteroaryl refers to
substitution of each of those groups individually as well as to
substitutions of combinations of those groups. That is, if R.sup.1
is arylalkyl, the aryl portion may be unsubstituted or substituted
with at least one substituent, such as one, two, three, or four
substituents, independently selected from R.sup.6b and the alkyl
portion may also be unsubstituted or substituted with at least one
substituent, such as one, two, three, or four substituents,
independently selected from R.sup.6a.
The term "pharmaceutically acceptable salts" refers to salts
prepared from pharmaceutically acceptable non-toxic bases or acids
including inorganic or organic bases and inorganic or organic
acids. Salts derived from inorganic bases may be selected, for
example, from aluminum, ammonium, calcium, copper, ferric, ferrous,
lithium, magnesium, manganic, manganous, potassium, sodium, and
zinc salts. Further, for example, the pharmaceutically acceptable
salts derived from inorganic bases may be selected from ammonium,
calcium, magnesium, potassium, and sodium salts. Salts in the solid
form may exist in one or more crystal structures, and may also be
in the form of hydrates. Salts derived from pharmaceutically
acceptable organic non-toxic bases may be selected, for example,
from salts of primary, secondary, and tertiary amines, substituted
amines including naturally occurring substituted amines, cyclic
amines, and basic ion exchange resins, such as arginine, betaine,
caffeine, choline, N,N'-dibenzylethylene-diamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine
resins, procaine, purines, theobromine, triethylamine,
trimethylamine, and tripropylamine, tromethamine.
When the compound disclosed herein is basic, salts may be prepared
using at least one pharmaceutically acceptable non-toxic acid,
selected from inorganic and organic acids. Such acid may be
selected, for example, from acetic, benzenesulfonic, benzoic,
camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,
glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic,
malic, mandelic, methanesulfonic, mucic, nitric, pamoic,
pantothenic, phosphoric, succinic, sulfuric, tartaric, and
p-toluenesulfonic acids. In some embodiments, such acid may be
selected, for example, from citric, hydrobromic, hydrochloric,
maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
The term "protecting group" or "Pg" refers to a substituent that
can be commonly employed to block or protect a certain
functionality while reacting other functional groups on the
compound. For example, an "amino-protecting group" is a substituent
attached to an amino group that blocks or protects the amino
functionality in the compound. Suitable amino-protecting groups
include but are not limited to acetyl, trifluoroacetyl,
t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and
9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a
"hydroxy-protecting group" refers to a substituent of a hydroxy
group that blocks or protects the hydroxy functionality. Suitable
protecting groups include but are not limited to acetyl and silyl.
A "carboxy-protecting group" refers to a substituent of the carboxy
group that blocks or protects the carboxy functionality. Common
carboxy-protecting groups include --CH2CH2SO2Ph, cyanoethyl,
2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl,
2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl,
2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a general
description of protecting groups and their use, see T. W. Greene,
Protective Groups in Organic Synthesis, John Wiley & Sons, New
York, 1991.
The terms "administration of" and or "administering" at least one
compound and/or at least one pharmaceutically acceptable salt
should be understood to mean providing at least one compound and/or
at least one pharmaceutically acceptable salt thereof to the
individual in recognized need of treatment.
The term "effective amount" means the amount of the at least one
compound and/or at least one pharmaceutically acceptable salt that
will elicit the biological or medical response of a tissue, system,
animal or human that is being sought by the researcher,
veterinarian, medical doctor or other clinician.
The term "composition" as used herein is intended to encompass a
product comprising the specified ingredients in the specified
amounts, as well as any product which results, directly or
indirectly, from combination of the specified ingredients in the
specified amounts. Such term in relation to a pharmaceutical
composition is intended to encompass a product comprising the
active ingredient (s), and the inert ingredient (s) that make up
the carrier, as well as any product which results, directly or
indirectly, from combination, complexation or aggregation of any
two or more of the ingredients, or from dissociation of one or more
of the ingredients, or from other types of reactions or
interactions of one or more of the ingredients.
The term "pharmaceutically acceptable" it is meant compatible with
the other ingredients of the formulation and not unacceptably
deleterious to the recipient thereof.
Disclosed herein is at least one compound of formula (I):
##STR00006## and/or at least one pharmaceutically acceptable salt
thereof, wherein:
X is C or N;
Y is CR.sup.11, O, S, or NR.sup.12;
6-5 membered fused ring system A-B is selected from:
##STR00007##
Q is selected from aryl and heteroaryl;
R.sup.1 is selected from: hydrogen, C.sub.1-10 alkyl, C.sub.2-10
alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4
alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, and
heteroaryl-C.sub.1-4 alkyl, wherein alkyl, alkenyl, alkynyl,
cycloalkyl, and heterocyclyl are each unsubstituted or substituted
with at least one substituent, such as one, two, three, or four
substituents, independently selected from R.sup.6a, and wherein
aryl and heteroaryl are each unsubstituted or substituted with at
least one substituent, such as one, two, three, or four
substituents, independently selected from R.sup.6b;
R.sup.2 is selected from: hydrogen, halogen, hydroxyl, CN,
C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl,
C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl,
heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4
alkyl, heteroaryl, and heteroaryl-C.sub.1-4 alkyl, wherein alkyl,
alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each
unsubstituted or substituted with at least one substituent, such as
one, two, three, or four substituents, independently selected from
R.sup.6a, and each aryl and heteroaryl is unsubstituted or
substituted with at least one substituent, such as one, two, three,
or four substituents, independently selected from R.sup.6b;
R.sup.3 and R.sup.4 are independently selected from: hydrogen,
C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, and
C.sub.3-10 cycloalkyl; wherein alkyl, alkenyl, alkynyl, and
cycloalkyl are each unsubstituted or substituted with at least one
substituent, such as one, two, three, or four substituents,
independently selected from R.sup.6a; or R.sup.3 and R.sup.4
together with the nitrogen atoms to which they are attached form a
4-12 membered ring containing 0, 1, 2 or 3 heteroatoms
independently selected from oxygen, sulfur and nitrogen, and
optionally substituted with 1 or 2 R.sup.6a groups;
with the proviso that when R.sup.3 and R.sup.4 are both hydrogen,
R.sup.2 is not aryl or heteroaryl;
each R.sup.5 is independently selected from: hydrogen, C.sub.1-10
alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10
cycloalkyl, --OR.sup.8, --NR.sup.7S(O).sub.rR.sup.8, --NO.sub.2,
-halogen, --S(O).sub.rR.sup.7, --SR.sup.8, --S(O).sub.2OR.sup.7,
--OS(O).sub.2R.sup.8, --S(O).sub.rNR.sup.7R.sup.8,
--NR.sup.7R.sup.8, --O(CR.sup.9R.sup.10).sub.tNR.sup.7R.sup.8,
--C(O)R.sup.7, --CO.sub.2R.sup.8,
--CO.sub.2(CR.sup.9R.sup.10).sub.tCONR.sup.7R.sup.8,
--OC(O)R.sup.7, --CN, --C(O)NR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8,
--OC(O)NR.sup.7R.sup.8, --NR.sup.7C(O)OR.sup.8,
--NR.sup.7C(O)NR.sup.7R.sup.8, --CR.sup.7(N--OR.sup.8),
--CHF.sub.2, --CF.sub.3, --OCHF.sub.2, and --OCF.sub.3; wherein
C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, and
C.sub.3-10 cycloalkyl are each unsubstituted or substituted with at
least one substituent, such as one, two, three, or four
substituents, independently selected from R.sup.6a;
each R.sup.6a is independently selected from: --C.sub.1-10 alkyl,
--C.sub.2-10 alkenyl, --C.sub.2-10 alkynyl, --C.sub.3-10
cycloalkyl, --OR.sup.8, --NR.sup.7S(O).sub.rR.sup.8, --NO.sub.2,
-halogen, --S(O).sub.rR.sup.7, --SR.sup.8, --S(O).sub.2OR.sup.7,
--OS(O).sub.2R.sup.8, --S(O).sub.rNR.sup.7R.sup.8,
--NR.sup.7R.sup.8, --(CR.sup.9R.sup.10).sub.tOR.sup.8',
--(CR.sup.9R.sup.10).sub.tNR.sup.7R.sup.8,
--(CR.sup.9R.sup.10).sub.tSR.sup.8,
--(CR.sup.9R.sup.10).sub.tS(O).sub.rR.sup.8,
--(CR.sup.9R.sup.10).sub.tCO.sub.2R.sup.8,
--(CR.sup.9R.sup.10).sub.tCONR.sup.7R.sup.8,
--(CR.sup.9R.sup.10).sub.tNR.sup.7CO.sub.2R.sup.8,
--(CR.sup.9R.sup.10).sub.tOCONR.sup.7R.sup.8,
--(CR.sup.9R.sup.10).sub.tNR.sup.7CONR.sup.7R.sup.8,
--(CR.sup.9R.sup.10).sub.tNR.sup.7SO.sub.2NR.sup.7R.sup.8,
--O(CR.sup.9R.sup.10).sub.tNR.sup.7R.sup.8, --C(O)R.sup.7,
--C(O)(CR.sup.9R.sup.10).sub.tOR.sup.8,
--C(O)(CR.sup.9R.sup.10).sub.tNR.sup.7R.sup.8,
--C(O)(CR.sup.9R.sup.10).sub.tSR.sup.8,
--C(O)(CR.sup.9R.sup.10).sub.tS(O).sub.rR.sup.8, --CO.sub.2R.sup.8,
--CO.sub.2(CR.sup.9R.sup.10).sub.tCONR.sup.7R.sup.8,
--OC(O)R.sup.7, --CN, --C(O)NR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8,
--OC(O)NR.sup.7R.sup.8, --NR.sup.7C(O)OR.sup.8,
--NR.sup.7C(O)NR.sup.7R.sup.8, --CR.sup.7(N--OR.sup.8),
--CHF.sub.2, --CF.sub.3, --OCHF.sub.2, and --OCF.sub.3;
each R.sup.6b is independently selected from: R.sup.6a, aryl,
aryl-C.sub.1-4 alkyl, heteroaryl, and heteroaryl-C.sub.1-4
alkyl;
each R.sup.7 and each R.sup.8 are independently selected from:
hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl,
cycloalkyl, cycloalkyl-C.sub.1-4 alkyl, heterocyclyl,
heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl,
heteroaryl, and heteroaryl-C.sub.1-4 alkyl; wherein alkyl, alkenyl,
alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or
substituted with at least one substituent, such as one, two, three,
or four substituents, independently selected from R.sup.6a, and
aryl and heteroaryl are each unsubstituted or substituted with at
least one substituent, such as one, two, three, or four
substituents, independently selected from R.sup.6b; or R.sup.7 and
R.sup.8 together with the atom(s) to which they are attached form a
heterocyclic ring of 4 to 12 members containing 0, 1, or 2
additional heteroatoms independently selected from oxygen, sulfur
and nitrogen, and optionally substituted with 1 or 2 R.sup.6b
groups;
each R.sup.9 and each R.sup.10 are independently selected from:
hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl,
cycloalkyl, cycloalkyl-C.sub.1-4 alkyl, heterocyclyl,
heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl,
heteroaryl, and heteroaryl-C.sub.1-4 alkyl; or R.sup.9 and R.sup.10
together with the carbon atom(s) to which they are attached form a
ring of 3 to 7 members containing 0, 1, or 2 heteroatoms
independently selected from oxygen, sulfur and nitrogen, and
optionally substituted with 1 or 2 R.sup.6a groups;
R.sup.11 is selected from: hydrogen, C.sub.1-10 alkyl, C.sub.3-10
cycloalkyl, C.sub.3-10 cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl,
heteroaryl-C.sub.1-4 alkyl, --OR.sup.7,
--NR.sup.7S(O).sub.rR.sup.8, --S(O).sub.rR.sup.7, --SR.sup.7,
--S(O).sub.2OR.sup.7, --OS(O).sub.2R.sup.7,
--S(O).sub.rNR.sup.7R.sup.8, --NR.sup.7R.sup.8,
--O(CR.sup.9R.sup.10).sub.tNR.sup.7R.sup.8, --C(O)R.sup.7,
--CO.sub.2R.sup.8,
--CO.sub.2(CR.sup.9R.sup.10).sub.tCONR.sup.7R.sup.8,
--OC(O)R.sup.7, --CN, --C(O)NR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8,
--OC(O)NR.sup.7R.sup.8, --NR.sup.7C(O)OR.sup.8,
--NR.sup.7C(O)NR.sup.7R.sup.8, --CHF.sub.2, --CF.sub.3,
--OCHF.sub.2, and --OCF.sub.3;
R.sup.12 is selected from: hydrogen, C.sub.1-10 alkyl, C.sub.3-10
cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl,
heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl,
heteroaryl, heteroaryl-C.sub.1-4 alkyl, --S(O).sub.rR.sup.7,
--C(O)R.sup.7, --CO.sub.2R.sup.7,
--CO.sub.2(CR.sup.9R.sup.10).sub.tCONR.sup.7R.sup.8, and
--C(O)NR.sup.7R.sup.8;
m is independently selected from 0, 1, 2, and 3;
each r is independently selected from 1 and 2;
each t is independently selected from 1, 2, and 3.
In some embodiments, 6-5 membered fused ring system A-B is
##STR00008## wherein each R.sup.12 and each R.sup.11 are
independently selected from hydrogen and C.sub.1-10 alkyl.
Preferably each R.sup.12 and each R.sup.11 are independently
selected from hydrogen and methyl.
In some embodiments, Q is selected from heteroaryl.
In some embodiments, Q is selected from pyridyl, pyridazinyl and
5,6,7,8-tetrahydro-1,6-naphthyridinyl. Preferably Q is selected
from pyridin-2-yl, pyridazin-3-yl and
5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl. More preferably Q is
pyridin-2-yl.
In some embodiments, R.sup.1 is selected from hydrogen, C.sub.1-10
alkyl, heterocyclyl and heterocyclyl-C.sub.1-4 alkyl, wherein
heterocyclyl is unsubstituted or substituted with at least one,
such as 1, 2, 3 or 4, substituents independently selected from
R.sup.6a, wherein each R.sup.6a is independently selected from
C.sub.1-10 alkyl, --NR.sup.7R.sup.8,
--(CR.sup.9R.sup.10).sub.tOR.sup.8, --OR.sup.8, --C(O)R.sup.7,
--(CR.sup.9R.sup.10).sub.tS(O).sub.rR.sup.8; wherein R.sup.7,
R.sup.8, R.sup.9, R.sup.10, t and r are described as above.
In some embodiments, Q is selected from pyridin-2-yl,
pyridazin-3-yl, R.sup.1 is selected from heterocyclyl and
heterocyclyl-C.sub.1-4alkyl groups consisting of the following
groups:
##STR00009## wherein each heterocyclyl is unsubstituted or
substituted with at least one, such as 1, 2, 3 or 4 substituents
independently selected from R.sup.6a, wherein each R.sup.6a is
independently selected from C.sub.1-10 alkyl, --NR.sup.7R.sup.8,
--(CR.sup.9R.sup.10).sub.tOR.sup.8, --OR.sup.8, --C(O)R.sup.7,
--C(O)NR.sup.7R.sup.8, --(CR.sup.9R.sup.10).sub.tS(O).sub.rR.sup.8;
wherein R.sup.7, R.sup.8, R.sup.9, R.sup.10, t and r are described
as above.
Preferably, R.sup.6a is independently selected from hydrogen,
methyl, ethyl, hydroxyl, hydroxymethyl, hydroxyethyl, acetyl,
hydroxyacetyl, methoxymethyl, methoxyethyl, hydroxyacetyl,
(methylsulfonyl)ethyl, amino, carbamoyl, methylamino, and
dimethylamino.
In some embodiments, Q is selected from
5,6,7,8-tetrahydro-1,6-naphthyridinyl, R.sup.1 is selected from
hydrogen, C.sub.1-10 alkyl.
In some embodiments, R.sup.2 is selected from C.sub.3-10
cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with
at least one, such as 1, 2, 3, or 4, substituents independently
selected from R.sup.6a.
In some embodiments, R.sup.2 is selected from cyclopentyl and
cyclohexyl, wherein cyclohexyl is unsubstituted or substituted with
methyl. Preferably R.sup.2 is selected from cyclopentyl and
4-methylcyclohexyl.
In some embodiments, R.sup.3 and R.sup.4 are independently selected
from hydrogen, C.sub.1-10 alkyl and C.sub.3-10 cycloalkyl, with the
proviso that when R.sup.3 and R.sup.4 are both hydrogen, R.sup.2 is
not aryl or heteroaryl. Preferably R.sup.3 and R.sup.4 are
independently selected from hydrogen, methyl, ethyl, and
cyclopropyl, with the proviso that when R.sup.3 and R.sup.4 are
both hydrogen, R.sup.2 is not aryl or heteroaryl.
In some embodiments, R.sup.3 and R.sup.4 together with the nitrogen
atoms to which they are attached form azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl, and morpholino, wherein the formed ring
is unsubstituted or substituted with methyl, hydroxyl, and
methoxy.
In some embodiments, R.sup.5 is independently selected from
hydrogen, C.sub.1-10 alkyl and --C(O)R.sup.7. wherein R.sup.7 is
selected from methyl and hydroxymethyl.
In some embodiments, Q is selected from pyridin-2-yl,
pyridazin-3-yl, R.sup.5 is hydrogen.
In some embodiments, Q is selected from
5,6,7,8-tetrahydro-1,6-naphthyridinyl, R.sup.5 is independently
selected from hydrogen, C.sub.1-10 alkyl and --C(O)R.sup.7. wherein
R.sup.7 is selected from methyl and hydroxymethyl.
Also provided is at least one compound, selected from:
7-cyclopentyl-N,N-dimethyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)thieno[-
3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino-
)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)-5H-pyr-
rolo[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino-
)-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrro-
lo[2,1-f][1,2,4]triazine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)ami-
no)pyrrolo[2, 1-f][1,2,4]triazine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)furo[-
3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)ami-
no)furo[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N,5-trimethyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)-5H--
pyrrolo[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N,5-trimethyl-2-(5-(4-methylpiperazin-1-yl)pyridin-2-ylam-
ino)-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide,
(S)-7-cyclopentyl-N,N-dimethyl-2-((5-(3-oxotetrahydro-3H-oxazolo[3,4-a]py-
razin-7(1H)-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
(R)-7-cyclopentyl-N,N-dimethyl-2-((5-(3-oxotetrahydro-3H-oxazolo[3,4-a]py-
razin-7(1H)-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
(R)-7-cyclopentyl-N,N-dimethyl-2-((5-(morpholin-2-yl)pyridin-2-yl)amino)t-
hieno[3,2-d]pyrimidine-6-carboxamide,
2-((5-(4-aminopiperidin-1-yl)pyridin-2-yl)amino)-7-cyclopentyl-N,N-dimeth-
ylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(4-(methylamino)piperidin-1-yl)pyridin-2-
-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-2-((5-(4-(dimethylamino)piperidin-1-yl)pyridin-2-yl)amino)--
N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(S)-7-cyclopentyl-2-((5-(3-(methoxymethyl)piperazin-1-yl)pyridin-2-yl)ami-
no)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(S)-7-cyclopentyl-2-((5-(3-(methoxymethyl)-4-methylpiperazin-1-yl)pyridin-
-2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(S)-7-cyclopentyl-2-((5-(4-ethyl-3-(methoxymethyl)piperazin-1-yl)pyridin--
2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(S)-7-cyclopentyl-2-((5-(3-(hydroxymethyl)piperazin-1-yl)pyridin-2-yl)ami-
no)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(S)-7-cyclopentyl-2-((5-(3-(hydroxymethyl)-4-methylpiperazin-1-yl)pyridin-
-2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(S)-7-cyclopentyl-2-((5-(4-ethyl-3-(hydroxymethyl)piperazin-1-yl)pyridin--
2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(R)-7-cyclopentyl-2-((5-(3-(methoxymethyl)piperazin-1-yl)pyridin-2-yl)ami-
no)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(R)-7-cyclopentyl-2-((5-(3-(methoxymethyl)-4-methylpiperazin-1-yl)pyridin-
-2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(R)-7-cyclopentyl-2-((5-(4-ethyl-3-(methoxymethyl)piperazin-1-yl)pyridin--
2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(R)-7-cyclopentyl-2-((5-(3-(hydroxymethyl)piperazin-1-yl)pyridin-2-yl)ami-
no)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(R)-7-cyclopentyl-2-((5-(3-(hydroxymethyl)-4-methylpiperazin-1-yl)pyridin-
-2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(R)-7-cyclopentyl-2-((5-(4-ethyl-3-(hydroxymethyl)piperazin-1-yl)pyridin--
2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)thien-
o[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)ami-
no)thieno[3,2-d]pyrimidine-6-carboxamide,
2-((5-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)amino)-7-cyclop-
entyl-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-ylmethyl)pyridin-2-yl)amino-
)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-((4-methylpiperazin-1-yl)methyl)pyridin--
2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-N,-
N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
2-((5-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)amino)-7-c-
yclopentyl-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1-
]heptan-2-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
(R)-7-cyclopentyl-2-((5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin--
2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
(S)-7-cyclopentyl-2-((5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin--
2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
2-((5-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)amino)-7-c-
yclopentyl-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
2-((5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-2-yl)amino)-7-cyclopent-
yl-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(6-methyl-3,6-diazabicyclo[3.1.1]heptan--
3-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-2-((5-(6-ethyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-2-
-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-2-((5-((7R,8aR)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1-
H)-yl)pyridin-2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamid-
e,
7-cyclopentyl-2-((5-((7S,8aR)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2-
(1H)-yl)pyridin-2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxam-
ide,
7-cyclopentyl-2-((5-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-
-2(1H)-yl)pyridin-2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carbox-
amide,
2-((5-(3,6-diazabicyclo[3.2.0]heptan-3-yl)pyridin-2-yl)amino)-7-cyc-
lopentyl-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(6-methyl-3,6-diazabicyclo[3.2.0]heptan--
3-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-2-((5-(6-ethyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)pyridin-2-
-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((6-(piperazin-1-yl)pyridazin-3-yl)amino)thi-
eno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((6-(4-methylpiperazin-1-yl)pyridazin-3-yl)a-
mino)thieno[3,2-d]pyrimidine-6-carboxamide,
2-((6-(4-acetylpiperazin-1-yl)pyridazin-3-yl)amino)-7-cyclopentyl-N,N-dim-
ethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-2-((6-(4-(2-hydroxyacetyl)piperazin-1-yl)pyridazin-3-yl)ami-
no)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((6-(4-(2-(methyl
sulfonyl)ethyl)piperazin-1-yl)pyridazin-3-yl)amino)thieno[3,2-d]pyrimidin-
e-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)a-
mino)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((6-methyl-5,6,7,8-tetrahydro-1,6-naphthyrid-
in-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-2-((5-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-2-yl)amino)-
-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-2-((5-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-2-yl)amino)-
-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(4-(2-(methyl
sulfonyl)ethyl)piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine--
6-carboxamide,
7-cyclopentyl-2-((5-(4-ethylpiperazin-1-yl)pyridin-2-yl)amino)-N,N-dimeth-
ylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-2-((5-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)amin-
o)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide
7-cyclopentyl-N,N-dimethyl-2-((5-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)p-
yridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide
7-cyclopentyl-2-((5-((3S,5R)-4-ethyl-3,5-dimethylpiperazin-1-yl)pyridin-2-
-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide
7-cyclopentyl-N,N-dimethyl-2-((5-(1-methyl-2,4-dioxo-1,3,8-triazaspiro[4.-
5]decan-8-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide
2-((5-(4-carbamoyl-4-(methyl
amino)piperidin-1-yl)pyridin-2-yl)amino)-7-cyclopentyl-N,N-dimethylthieno-
[3,2-d]pyrimidine-6-carboxamide
azetidin-1-yl(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thie-
no[3,2-d]pyrimidin-6-yl)methanone,
(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyri-
midin-6-yl)(3-methoxyazetidin-1-yl)methanone,
(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyri-
midin-6-yl)(3-hydroxyazetidin-1-yl)methan one,
(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyri-
midin-6-yl)(piperidin-1-yl)methanone,
(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyri-
midin-6-yl)(4-methylpiperazin-1-yl)methanone,
(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyri-
midin-6-yl)(piperazin-1-yl)methanone,
7-cyclopentyl-N-cyclopropyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thie-
no[3,2-d]p yrimidine-6-carboxamide,
(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyri-
midin-6-yl)(pyrrolidin-1-yl)methanone,
7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrim-
idine-6-carboxamide,
7-cyclopentyl-N-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,-
2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N-ethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-
-d]pyrimidine-6-carboxamide,
(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyri-
midin-6-yl)(morpholino)methanone,
azetidin-1-yl(7-cyclopentyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)am-
ino)thieno[3,2-d]pyrimidin-6-yl)methanone,
(7-cyclopentyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)thieno[3,-
2-d]pyrimidin-6-yl)(3-methoxyazetidin-1-yl)methanone,
(7-cyclopentyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)thieno[3,-
2-d]pyrimidin-6-yl)(piperidin-1-yl)methanone,
(7-cyclopentyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)thieno[3,-
2-d]pyrimidin-6-yl)(4-methylpiperazin-1-yl)methanone,
7-cyclopentyl-N-cyclopropyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)am-
ino)thieno[3,2-d]pyrimidine-6-carboxamide,
(7-cyclopentyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)thieno[3,-
2-d]pyrimidin-6-yl)(pyrrolidin-1-yl)methanone,
7-cyclopentyl-N-methyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)t-
hieno[3,2-d]pyrimidine-6-carboxamide,
(7-cyclopentyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)thieno[3,-
2-d]pyrimidin-6-yl)(morpholino)methanone,
N,N-dimethyl-7-((1r,4r)-4-methylcyclohexyl)-2-((5-(piperazin-1-yl)pyridin-
-2-yl)amino) thieno[3,2-d]pyrimidine-6-carboxamide,
N,N-dimethyl-7-((1r,4r)-4-methylcyclohexyl)-2-((5-(4-methylpiperazin-1-yl-
)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
N,N-dimethyl-7-((1r,4r)-4-methylcyclohexyl)-2-((5,6,7,8-tetrahydro-1,6-na-
phthyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
N,N-dimethyl-2-((6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino)-
-7-((1r,4r)-4-methylcyclohexyl)thieno[3,2-d]pyrimidine-6-carboxamide,
2-((6-acetyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino)-N,N-dimethyl-
-7-((1r,4r)-4-methylcyclohexyl)thieno[3,2-d]pyrimidine-6-carboxamide,
2-((6-(2-hydroxyacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino)-N-
,N-dimethyl-7-((1r,4r)-4-methylcyclohexyl)thieno[3,2-d]pyrimidine-6-carbox-
amide,
N,N-dimethyl-7-((1r,4r)-4-methylcyclohexyl)-2-((6-(piperazin-1-yl)p-
yridazin-3-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
N,N-dimethyl-7-((1r,4r)-4-methylcyclohexyl)-2-((6-(4-methylpiperazin-1-yl-
)pyridazin-3-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
2-((6-(4-acetylpiperazin-1-yl)pyridazin-3-yl)amino)-N,N-dimethyl-7-((1r,4-
r)-4-methylcyclohexyl)thieno[3,2-d]pyrimidine-6-carboxamide,
2-((6-(4-(2-hydroxyacetyl)piperazin-1-yl)pyridazin-3-yl)amino)-N,N-dimeth-
yl-7-((1
r,4r)-4-methylcyclohexyl)thieno[3,2-d]pyrimidine-6-carboxamide,
and pharmaceutically acceptable salts thereof.
In another of its aspects, there is provided a pharmaceutical
composition comprising a compound according to any one of the above
embodiments and variations, wherein the composition is adapted for
administration by a route selected from the group consisting of
orally, parenterally, intraperitoneally, intravenously,
intraarterially, transdermally, sublingually, intramuscularly,
rectally, transbuccally, intranasally, liposomally, via inhalation,
vaginally, intraoccularly, via local delivery (for example by
catheter or stent), subcutaneously, intraadiposally,
intraarticularly, and intrathecally.
In yet another of its aspects, there is provided a kit comprising a
compound of any one of the above embodiments and variations; and
instructions which comprise one or more forms of information
selected from the group consisting of indicating a disease state
for which the composition is to be administered, storage
information for the composition, dosing information and
instructions regarding how to administer the composition. In one
particular variation, the kit comprises the compound in a multiple
dose form.
In still another of its aspects, there is provided an article of
manufacture comprising a compound of any one of the above
embodiments and variations; and packaging materials. In one
variation, the packaging material comprises a container for housing
the compound. In one particular variation, the container comprises
a label indicating one or more members of the group consisting of a
disease state for which the compound is to be administered, storage
information, dosing information and/or instructions regarding how
to administer the compound. In another variation, the article of
manufacture comprises the compound in a multiple dose form.
In a further of its aspects, there is provided a therapeutic method
comprising administering a compound of any one of the above
embodiments and variations to a subject.
In another of its aspects, there is provided a method of inhibiting
a CDK4/6 kinase comprising contacting the CDK4/6 with a compound of
any one of the above embodiments and variations.
In yet another of its aspects, there is provided a method of
inhibiting a CDK4/6 comprising causing a compound of any one of the
above embodiments and variations to be present in a subject in
order to inhibit the CDK4/6 in vivo.
In a further of its aspects, there is provided a method of
inhibiting CDK4/6 comprising administering a first compound to a
subject that is converted in vivo to a second compound wherein the
second compound inhibits the CDK4/6 in vivo, the second compound
being a compound according to any one of the above embodiments and
variations.
In another of its aspects, there is provided a method of treating a
disease state for which a CDK4/6 possesses activity that
contributes to the pathology and/or symptomology of the disease
state, the method comprising causing a compound of any one of the
above embodiments and variations to be present in a subject in a
therapeutically effective amount for the disease state.
In a further of its aspects, there is provided a method of treating
a disease state for which a CDK4/6 possesses activity that
contributes to the pathology and/or symptomology of the disease
state, the method comprising administering a first compound to a
subject that is converted in vivo to a second compound wherein the
second compound inhibits the CDK4/6 in vivo. It is noted that the
compounds of the present invention may be the first or second
compounds.
In one variation of each of the above methods the disease state is
selected from the group consisting of cancerous hyperproliferative
disorders (e.g., brain, lung, squamous cell, bladder, gastric,
pancreatic, breast, head, neck, renal, kidney, ovarian, prostate,
colorectal, epidermoid, esophageal, testicular, gynecological or
thyroid cancer); non-cancerous hyperproliferative disorders (e.g.,
benign hyperplasia of the skin (e.g., psoriasis), restenosis, and
benign prostatic hypertrophy (BPH)); pancreatitis; kidney disease;
pain; preventing blastocyte implantation; treating diseases related
to vasculogenesis or angiogenesis (e.g., tumor angiogenesis, acute
and chronic inflammatory disease such as rheumatoid arthritis,
atherosclerosis, inflammatory bowel disease, skin diseases such as
psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy,
retinopathy of prematurity, age-related macular degeneration,
hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast,
lung, pancreatic; prostate, colon and epidermoid cancer); asthma;
neutrophil chemotaxis (e.g., reperfusion injury in myocardial
infarction and stroke and inflammatory arthritis); septic shock;
T-cell mediated diseases where immune suppression would be of value
(e.g., the prevention of organ transplant rejection, graft versus
host disease, lupus erythematosus, multiple sclerosis, and
rheumatoid arthritis); atherosclerosis; inhibition of keratinocyte
responses to growth factor cocktails; chronic obstructive pulmonary
disease (COPD) and other diseases.
In another of its aspects, there is provided a method of treating a
disease state for which a mutation in the CDK4/6 gene contributes
to the pathology and/or symptomology of the disease state
including, for example, melanomas, lung cancer, colon cancer and
other tumor types.
In still another of its aspects, the present invention relates to
the use of a compound of any of the above embodiments and
variations as a medicament. In yet another of its aspects, the
present invention relates to the use of a compound according to any
one of the above embodiments and variations in the manufacture of a
medicament for inhibiting a CDK4/6.
In a further of its aspects, the present invention relates to the
use of a compound according to any one of the above embodiments and
variations in the manufacture of a medicament for treating a
disease state for which a CDK4/6 possesses activity that
contributes to the pathology and/or symptomology of the disease
state.
Administration and Pharmaceutical Compositions
In general, compounds of the disclosure will be administered in
therapeutically effective amounts via any of the usual and
acceptable modes known in the art, either singly or in combination
with one or more therapeutic agents. A therapeutically effective
amount may vary widely depending on the severity of the disease,
the age and relative health of the subject, the potency of the
compound used and other factors known to those of ordinary skill in
the art. For example, for the treatment of neoplastic diseases and
immune system disorders, the required dosage will also vary
depending on the mode of administration, the particular condition
to be treated and the effect desired.
In general, satisfactory results are indicated to be obtained
systemically at daily dosages of from about 0.001 to about 100
mg/kg per body weight, or particularly, from about 0.03 to 2.5
mg/kg per body weight. An indicated daily dosage in the larger
mammal, e.g. humans, may be in the range from about 0.5 mg to about
2000 mg, or more particularly, from about 0.5 mg to about 1000 mg,
conveniently administered, for example, in divided doses up to four
times a day or in retard form. Suitable unit dosage forms for oral
administration comprise from ca. 1 to 50 mg active ingredient.
Compounds of the disclosure may be administered as pharmaceutical
compositions by any conventional route; for example, enterally,
e.g., orally, e.g., in the form of tablets or capsules;
parenterally, e.g., in the form of injectable solutions or
suspensions; or topically, e.g., in the form of lotions, gels,
ointments or creams, or in a nasal or suppository form.
Pharmaceutical compositions comprising a compound of the present
disclosure in free form or in a pharmaceutically acceptable salt
form in association with at least one pharmaceutically acceptable
carrier or diluent may be manufactured in a conventional manner by
mixing, granulating, coating, dissolving or lyophilizing processes.
For example, pharmaceutical compositions comprising a compound of
the disclosure in association with at least one pharmaceutical
acceptable carrier or diluent may be manufactured in conventional
manner by mixing with a pharmaceutically acceptable carrier or
diluent. Unit dosage forms for oral administration contain, for
example, from about 0.1 mg to about 500 mg of active substance.
In one embodiment, the pharmaceutical compositions are solutions of
the active ingredient, including suspensions or dispersions, such
as isotonic aqueous solutions. In the case of lyophilized
compositions comprising the active ingredient alone or together
with a carrier such as mannitol, dispersions or suspensions can be
made up before use. The pharmaceutical compositions may be
sterilized and/or contain adjuvants, such as preserving,
stabilizing, wetting or emulsifying agents, solution promoters,
salts for regulating the osmotic pressure and/or buffers. Suitable
preservatives include but are not limited to antioxidants such as
ascorbic acid, or microbicides, such as sorbic acid or benzoic
acid. The solutions or suspensions may further comprise
viscosity-increasing agents, including but not limited to, sodium
carboxymethyl cellulose, carboxymethylcellulose, dextran,
polyvinylpyrrolidone, gelatins, or solubilizers, e.g. Tween 80
(polyoxyethylene(20)sorbitan mono-oleate).
Suspensions in oil may comprise as the oil component the vegetable,
synthetic, or semi-synthetic oils customary for injection purposes.
Examples include liquid fatty acid esters that contain as the acid
component a long-chained fatty acid having from 8 to 22 carbon
atoms, or in some embodiments, from 12 to 22 carbon atoms. Suitable
liquid fatty acid esters include but are not limited to lauric
acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic
acid, margaric acid, stearic acid, arachidic acid, behenic acid or
corresponding unsaturated acids, for example oleic acid, elaidic
acid, erucic acid, brassidic acid and linoleic acid, and if
desired, may contain antioxidants, for example vitamin E,
3-carotene or 3,5-di-tert-butyl-hydroxytoluene. The alcohol
component of these fatty acid esters may have six carbon atoms and
may be monovalent or polyvalent, for example a mono-, di- or
trivalent, alcohol. Suitable alcohol components include but are not
limited to methanol, ethanol, propanol, butanol or pentanol or
isomers thereof; glycol and glycerol.
Other suitable fatty acid esters include but are not limited
ethyl-oleate, isopropyl myristate, isopropyl palmitate,
LABRAFIL.RTM. M 2375, (polyoxyethylene glycerol), LABRAFIL.RTM. M
1944 CS (unsaturated polyglycolized glycerides prepared by
alcoholysis of apricot kernel oil and comprising glycerides and
polyethylene glycol ester), LABRASOL.TM. (saturated polyglycolized
glycerides prepared by alcoholysis of TCM and comprising glycerides
and polyethylene glycol ester; all available from GaKefosse,
France), and/or MIGLYOL.RTM. 812 (triglyceride of saturated fatty
acids of chain length C8 to C12 from Huls AG, Germany), and
vegetable oils such as cottonseed oil, almond oil, olive oil,
castor oil, sesame oil, soybean oil, or groundnut oil.
Pharmaceutical compositions for oral administration may be
obtained, for example, by combining the active ingredient with one
or more solid carriers, and if desired, granulating a resulting
mixture, and processing the mixture or granules by the inclusion of
additional excipients, to form tablets or tablet cores.
Suitable carriers include but are not limited to fillers, such as
sugars, for example lactose, saccharose, mannitol or sorbitol,
cellulose preparations, and/or calcium phosphates, for example
tricalcium phosphate or calcium hydrogen phosphate, and also
binders, such as starches, for example corn, wheat, rice or potato
starch, methylcellulose, hydroxypropyl methylcellulose, sodium
carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if
desired, disintegrators, such as the above-mentioned starches,
carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic
acid or a salt thereof, such as sodium alginate. Additional
excipients include flow conditioners and lubricants, for example
silicic acid, talc, stearic acid or salts thereof, such as
magnesium or calcium stearate, and/or polyethylene glycol, or
derivatives thereof.
Tablet cores may be provided with suitable, optionally enteric,
coatings through the use of, inter alia, concentrated sugar
solutions which may comprise gum arable, talc,
polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide,
or coating solutions in suitable organic solvents or solvent
mixtures, or, for the preparation of enteric coatings, solutions of
suitable cellulose preparations, such as acetylcellulose phthalate
or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be
added to the tablets or tablet coatings, for example for
identification purposes or to indicate different doses of active
ingredient.
Pharmaceutical compositions for oral administration may also
include hard capsules comprising gelatin or soft-sealed capsules
comprising gelatin and a plasticizer, such as glycerol or sorbitol.
The hard capsules may contain the active ingredient in the form of
granules, for example in admixture with fillers, such as corn
starch, binders, and/or glidants, such as talc or magnesium
stearate, and optionally stabilizers. In soft capsules, the active
ingredient may be dissolved or suspended in suitable liquid
excipients, such as fatty oils, paraffin oil or liquid polyethylene
glycols or fatty acid esters of ethylene or propylene glycol, to
which stabilizers and detergents, for example of the
polyoxyethylene sorbitan fatty acid ester type, may also be
added.
Pharmaceutical compositions suitable for rectal administration are,
for example, suppositories comprising a combination of the active
ingredient and a suppository base. Suitable suppository bases are,
for example, natural or synthetic triglycerides, paraffin
hydrocarbons, polyethylene glycols or higher alkanols.
Pharmaceutical compositions suitable for parenteral administration
may comprise aqueous solutions of an active ingredient in
water-soluble form, for example of a water-soluble salt, or aqueous
injection suspensions that contain viscosity-increasing substances,
for example sodium carboxymethylcellulose, sorbitol and/or dextran,
and, if desired, stabilizers. The active ingredient, optionally
together with excipients, can also be in the form of a lyophilizate
and can be made into a solution before parenteral administration by
the addition of suitable solvents. Solutions such as are used, for
example, for parenteral administration can also be employed as
infusion solutions. The manufacture of injectable preparations is
usually carried out under sterile conditions, as is the filling,
for example, into ampoules or vials, and the sealing of the
containers.
The compounds of the disclosure may be administered as the sole
active ingredient, or together with other drugs useful against
neoplastic diseases or useful in immunomodulating regimens. For
example, the compounds of the disclosure may be used in accordance
with the disclosure in combination with pharmaceutical compositions
effective in various diseases as described above, e.g. with
cyclophosphamide, 5-fluorouracil, fludarabine, gemcitabine,
cisplatinum, carboplatin, vincristine, vinblastine, etoposide,
irinotecan, paclitaxel, docetaxel, rituxan, doxorubicine,
gefitinib, or imatinib; or also with cyclosporins, rapamycins,
ascomycins or their immunosuppressive analogs, e.g. cyclosporin A,
cyclosporin G, FK-506, sirolimus or everolimus, corticosteroids,
e.g. prednisone, cyclophosphamide, azathioprene, methotrexate, gold
salts, sulfasalazine, antimalarials, brequinar, leflunomide,
mizoribine, mycophenolic acid, mycophenolate, mofetil,
15-deoxyspergualine, immuno-suppressive monoclonal antibodies, e.g.
monoclonal antibodies to leukocyte receptors, e.g. MHC, CD2, CD3,
CD4, CD7, CD25, CD28, I CD40, CD45, CD58, CD80, CD86, CD152, CD137,
CD154, ICOS, LFA-1, VLA-4 or their ligands, or other
immunomodulatory compounds, e.g. CTLA41g.
The disclosure also provides for a pharmaceutical combinations,
e.g. a kit, comprising a) a first agent which is a compound of the
disclosure as disclosed herein, in free form or in pharmaceutically
acceptable salt form, and b) at least one co-agent. The kit can
comprise instructions for its administration.
EXAMPLES
Various methods may be developed for synthesizing the at least one
compound of formula (I) and/or at least one pharmaceutically
acceptable salt thereof. Representative methods for synthesizing
the at least one compound of formula (I) and/or at least one
pharmaceutically acceptable salt thereof are provided in the
Examples. It is noted, however, that the at least one compound of
formula (I) and/or at least one pharmaceutically acceptable salt
thereof may also be synthesized by other synthetic routes that
others may devise.
It will be readily recognized that certain compounds of formula (I)
have atoms with linkages to other atoms that confer a particular
stereochemistry to the compound (e.g., chiral centers). It is
recognized that synthesis of the at least one compound of formula
(I) and/or at least one pharmaceutically acceptable salt thereof
may result in the creation of mixtures of different stereoisomers
(enantiomers, diastereomers). Unless a particular stereochemistry
is specified, recitation of a compound is intended to encompass all
of the different possible stereoisomers.
The at least one compound of formula (I) can also be prepared as a
pharmaceutically acceptable acid addition salt by, for example,
reacting the free base form of the at least one compound with a
pharmaceutically acceptable inorganic or organic acid.
Alternatively, a pharmaceutically acceptable base addition salt of
the at least one compound of formula (I) can be prepared by, for
example, reacting the free acid form of the at least one compound
with a pharmaceutically acceptable inorganic or organic base.
Inorganic and organic acids and bases suitable for the preparation
of the pharmaceutically acceptable salts of compounds of formula
(I) are set forth in the definitions section of this Application.
Alternatively, the salt forms of the compounds of formula (I) can
be prepared using salts of the starting materials or
intermediates.
The free acid or free base forms of the compounds of formula (I)
can be prepared from the corresponding base addition salt or acid
addition salt form. For example, a compound of formula (I) in an
acid addition salt form can be converted to the corresponding free
base thereof by treating with a suitable base (e.g., ammonium
hydroxide solution, sodium hydroxide, and the like). A compound of
formula (I) in a base addition salt form can be converted to the
corresponding free acid thereof by, for example, treating with a
suitable acid (e.g., hydrochloric acid, etc).
The N-oxides of the at least one compound of formula (I) and/or at
least one pharmaceutically acceptable salt thereof can be prepared
by methods known to those of ordinary skill in the art. For
example, N-oxides can be prepared by treating an unoxidized form of
the compound of formula (I) with an oxidizing agent (e.g.,
trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic
acid, meta-chloroperoxybenzoic acid, or the like) in a suitable
inert organic solvent (e.g., a halogenated hydrocarbon such as
dichloromethane) at approximately 0 to 80.degree. C. Alternatively,
the N-oxides of the compounds of formula (I) can be prepared from
the N-oxide of an appropriate starting material.
Compounds of formula (I) in an unoxidized form can be prepared from
N-oxides of compounds of formula (I) by, for example, treating with
a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl
phosphine, lithium borohydride, sodium borohydride, phosphorus
trichloride, tribromide, and the like) in an suitable inert organic
solvent (e.g., acetonitrile, ethanol, aqueous dioxane, and the
like) at 0 to 80.degree. C.
Protected derivatives of the compounds of formula (I) can be made
by methods known to those of ordinary skill in the art. A detailed
description of the techniques applicable to the creation of
protecting groups and their removal can be found in T. W. Greene,
Protecting Groups in Organic Synthesis, 3rd edition, John Wiley
& Sons, Inc. 1999.
As used herein the symbols and conventions used in these processes,
schemes and examples are consistent with those used in the
contemporary scientific literature, for example, the Journal of the
American Chemical Society or the Journal of Biological Chemistry.
Standard single-letter or three-letter abbreviations are generally
used to designate amino acid residues, which are assumed to be in
the L-configuration unless otherwise noted. Unless otherwise noted,
all starting materials were obtained from commercial suppliers and
used without further purification. For example, the following
abbreviations may be used in the examples and throughout the
specification: g (grams); mg (milligrams); L (liters); mL
(milliliters); .mu.L (microliters); psi (pounds per square inch); M
(molar); mM (millimolar); i.v. (intravenous); Hz (Hertz); MHz
(megahertz); mol (moles); mmol (millimoles); RT (room temperature);
min (minutes); h (hours); mp (melting point); TLC (thin layer
chromatography); Rt (retention time); RP (reverse phase); MeOH
(methanol); i-PrOH (isopropanol); TEA (triethylamine); TFA
(trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF
(tetrahydrofuran); DMSO (dimethyl sulfoxide); EtOAc (ethyl
acetate); DME (1,2-dimethoxyethane); DCM (dichloromethane); DCE
(dichloroethane); DMF (N,N-dimethylformamide); DMPU
(N,N'-dimethylpropyleneurea); CDI (1,1-carbonyldiimidazole); IBCF
(isobutyl chloroformate); HOAc (acetic acid); HOSu
(N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); Et.sub.2O
(diethyl ether); EDCI
(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride); BOC
(tert-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl); DCC
(dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl); Ac (acetyl);
atm (atmosphere); TMSE (2-(trimethylsilyl)ethyl); TMS
(trimethylsilyl); TIPS (triisopropylsilyl); TBS
(t-butyldimethylsilyl); DMAP (4-dimethylaminopyridine); Me
(methyl); OMe (methoxy); Et (ethyl); tBu (tert-butyl); HPLC (high
pressure liquid chomatography); BOP
(bis(2-oxo-3-oxazolidinyl)phosphinic chloride); TBAF
(tetra-n-butylammonium fluoride); m-CPBA (meta-chloroperbenzoic
acid).
References to ether or Et.sub.2O are to diethyl ether; brine refers
to a saturated aqueous solution of NaCl. Unless otherwise
indicated, all temperatures are expressed in .degree. C. (degrees
Centigrade). All reactions were conducted under an inert atmosphere
at RT unless otherwise noted.
.sup.1H NMR spectra were recorded on a Varian Mercury Plus 400.
Chemical shifts are expressed in parts per million (ppm). Coupling
constants are in units of hertz (Hz). Splitting patterns describe
apparent multiplicities and are designated as s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), and br
(broad).
Low-resolution mass spectra (MS) and compound purity data were
acquired on a Shimadzu LC/MS single quadrapole system equipped with
electrospray ionization (ESI) source, UV detector (220 and 254 nm),
and evaporative light scattering detector (ELSD). Thin-layer
chromatography was performed on 0.25 mm E. Merck silica gel plates
(60F-254), visualized with UV light, 5% ethanolic phosphomolybdic
acid, ninhydrin, or p-anisaldehyde solution. Flash column
chromatography was performed on silica gel (230-400 mesh,
Merck).
Synthetic Schemes
Synthetic methods for preparing the compounds of the present
invention are illustrated in the following Schemes and Examples.
Starting materials are commercially available or may be made
according to procedures known in the art or as illustrated
herein.
Example 1
7-Cyclopentyl-N,N-dimethyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)thieno[3-
,2-d]pyrimidine-6-carboxamide (1)
##STR00010##
(5-Bromo-2-(methylthio)pyrimidin-4-yl)(cyclopentyl)methanol
(1a)
A mixture of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid
(2.49 g, 10.0 mmol) and cyclopentanecarbaldehyde (4.23 g, 43.2
mmol) in anisole (40 mL) was heated at 140.degree. C. for 7 h.
Solvent was evaporated under reduced pressure. The residue was
purified by silica gel column, eluted with 20-30% ethyl acetate in
hexanes to give
(5-bromo-2-(methylthio)pyrimidin-4-yl)(cyclopentyl)methanol (1a) as
pale yellow liquid (1.22 g, 40%). MS-ESI (m/z): 303 and 305 (1:1,
100%), [M+1].sup.+.
(5-Bromo-2-(methylthio)pyrimidin-4-yl)(cyclopentyl)methanone
(1b)
To a solution of 1a (1.15 g, 3.79 mmol) in anhydrous DCM (40 mL) at
0.degree. C. was added a Dess-Martin periodinane (2.90 g, 6.83
mmol). The mixture was stirred at room temperature for 2 h. The
reaction was diluted with saturated aqueous NaHCO.sub.3 (100 mL),
extracted with ethyl acetate (2.times.50 mL). The extracts were
washed with brine and dried (MgSO.sub.4). Solvents were evaporated
under reduced pressure. The residue was purified by silica gel
column, eluted with 10-20% ethyl acetate in hexanes to give
(5-bromo-2-(methylthio)pyrimidin-4-yl)(cyclopentyl)methanone (1b)
as pale yellow liquid (1.10 g, 96%). MS-ESI (m/z): 301 and 303
(1:1, 100%), [M+1].sup.+.
7-Cyclopentyl-2-(methylthio)thieno[3,2-d]pyrimidine-6-carboxylic
acid (1c)
To a solution of 1b (73.6 mg, 0.244 mmol) and methyl thioglycolate
(27.2 mg, 0.256 mmol) in DMF (1 mL) at room temperature was added
NaH (60%, 19.5 mg, 0.488 mmol). The mixture was stirred at room
temperature for 15 min. then heated at 60.degree. C. for 3 h. After
cooling to room temperature, 5 N NaOH (0.2 mL) was added and the
mixture was stirred for 1 h. The reaction was diluted with water
and 1 N HCl was added to pH=3.about.4. The mixture was extracted
with ethyl acetate (2.times.5 mL). The extracts were washed with
brine and dried (MgSO.sub.4). Solvents were evaporated under
reduced pressure to give crude
7-cyclopentyl-2-(methylthio)thieno[3,2-d]pyrimidine-6-carboxylic
acid (1c) as white solid (72.0 mg, 100%). MS-ESI (m/z): 295 (100%),
[M+1].sup.+. This was carried on to next reaction without further
purification.
7-Cyclopentyl-N,N-dimethyl-2-(methylthio)thieno[3,2-d]pyrimidine-6-carboxa-
mide (1d)
To a mixture of 1c (71.9 mg, 0.244 mmol), dimethylamine
hydrochloride (39.8 mg, 0.488 mmol), EDCI (70.3 mg, 0.366 mmol) and
HOBT hydrate (56.0 mg, 0.366 mmol) in anhydrous DMF (2 mL) was
added DIPEA (1.27 mL, 0.732 mmol). The mixture was stirred at room
temperature for 17 h. The mixture was diluted with water and
extracted with ethyl acetate (2.times.). The extracts were washed
with brine and dried (Na.sub.2SO.sub.4). Solvents were evaporated
under reduced pressure. The residue was purified by silica gel
column, eluted with 50% ethyl acetate in hexanes to give
7-cyclopentyl-N,N-dimethyl-2-(methylthio)thieno[3,2-d]pyrimidine-6-carbox-
amide (1d) as colorless oil (63.8 mg, 81%). MS-ESI (m/z): 322
(100%), [M+1].sup.+.
7-Cyclopentyl-N,N-dimethyl-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-car-
boxamide (1e)
To a solution of 1d (63.0 mg, 0.196 mmol) in dichloromethane (4 mL)
at 0.degree. C. was added mCPBA (75%, 113 mg, 0.490 mmol). The
mixture was stirred at room temperature for 1 h. Saturated aqueous
NaHSO.sub.3 (2 mL) was added and stirred for 10 min. The mixture
was diluted with saturated aqueous NaHCO.sub.3 (10 mL) and
extracted with DCM (2.times.10 mL). The extracts were dried
(Na.sub.2SO.sub.4). Solvents were evaporated under reduced pressure
to give crude 7-cyclopentyl-N,N-dimethyl-2-(methyl
sulfonyl)thieno[3,2-d]pyrimidine-6-carboxamide (1e) as white solid
(69.3 mg, 100%). MS-ESI (m/z): 354 [M+1].sup.+.
tert-Butyl
4-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)thieno[3,2-d]pyrimidin-
-2-ylamino)pyridin-3-yl)piperazine-1-carboxylate (1f)
To a solution of tert-butyl
4-(6-formamidopyridin-3-yl)piperazine-1-carboxylate (48.8 mg, 0.159
mmol) in DMF (0.5 mL) at room temperature was added NaH (60%, 10
mg, 0.25 mmol). The mixture was stirred at room temperature for 20
min. A solution of 1e (51.2 mg, 0.145 mmol) in DMF (0.5 mL) was
added. The mixture was stirred at room temperature for 1 h.
Methanol (3 mL) was added and stirred for 30 min. The mixture was
diluted with water (10 mL) and extracted with ethyl acetate
(2.times.10 mL). The extracts were dried (Na.sub.2SO.sub.4).
Solvents were evaporated under reduced pressure to give crude
tert-butyl
4-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)thieno[3,2-d]pyrimidin-2-ylamino-
) pyridin-3-yl)piperazine-1-carboxylate (If) as white solid (90
mg), which contains some inseparable impurities. MS-ESI (m/z): 552
[M+1].sup.+.
7-Cyclopentyl-N,N-dimethyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)thieno[3-
,2-d]pyrimidine-6-carboxamide (1)
To a solution of crude 1f (80 mg) in dichloromethane (3 mL) was
added TFA (3 mL). The mixture was stirred at room temperature for 1
h. Solvents were evaporated under reduced pressure. The residue was
purified by silica gel column, eluted with 94:5:1
DCM/methanol/ammonia to give
7-cyclopentyl-N,N-dimethyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)thieno[-
3,2-d]pyrimidine-6-carboxamide (1) as pale yellow solid (32.8 mg,
50%, 2 steps). MS-ESI (m/z): 452 [M+1].sup.+.
Example 2
7-Cyclopentyl-N,N-dimethyl-2-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-
thieno[3,2-d]pyrimidine-6-carboxamide (2)
##STR00011##
To a solution of 1 (15.3 mg, 0.034 mmol) in 1,2-dichloroethane (1
mL) at room temperature was added formaldehyde (37% in water, 14
mg, 0.17 mmol) followed by NaBH(OAc).sub.3 (9.3 mg, 0.044 mmol).
The mixture was stirred at room temperature for 30 min. The mixture
was diluted with saturated aqueous NaHCO.sub.3 (50 mL) and
extracted with DCM (2.times.5 mL). The extracts were dried
(Na.sub.2SO.sub.4). Solvents were evaporated under reduced
pressure. The residue was purified by silica gel column, eluted
with 96:3:1 DCM/methanol/ammonia to give
7-cyclopentyl-N,N-dimethyl-2-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino-
)thieno[3,2-d]pyrimidine-6-carboxamide (2) as pale yellow solid
(13.5 mg, 85%). MS-ESI (m/z): 466 [M+1].sup.+.
Example 3
7-Cyclopentyl-N,N-dimethyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)-5H-pyrr-
olo[3,2-d]pyrimidine-6-carboxamide (3)
##STR00012##
tert-Butyl
2-(4-(cyclopentanecarbonyl)-2-(methylthio)pyrimidin-5-ylamino)
acetate (3a)
A mixture of
(5-bromo-2-(methylthio)pyrimidin-4-yl)(cyclopentyl)methanone (1b,
752 mg, 2.50 mmol), glycine t-butyl ester hydrochloride (502 mg,
3.00 mmol), Pd.sub.2(dba).sub.3 (229 mg, 0.25 mmol), xantphos (145
mg, 0.25 mmol) and Cs.sub.2CO.sub.3 (2.61 g, 8.00 mmol) in dioxane
(25 mL) was heated under nitrogen at 90.degree. C. for 16 h. The
mixture was cooled to room temperature and diluted with water. This
was extracted with ethyl acetate (2.times.), washed with brine and
dried (Na.sub.2SO.sub.4). Solvent was evaporated under reduced
pressure. The residue was purified by silica gel column, eluted
with 20-30% ethyl acetate in hexanes to give tert-butyl
2-(4-(cyclopentanecarbonyl)-2-(methylthio)pyrimidin-5-ylamino)acetate
(3a) as yellow solid (460 mg, 52%). MS-ESI (m/z): 352
[M+1].sup.+.
tert-Butyl
2-(N-(4-(cyclopentanecarbonyl)-2-(methylthio)pyrimidin-5-yl)
acetamido)acetate (3b)
To a solution of 3a (272 mg, 0.775 mmol) in anhydrous DCM (8 mL)
was added pyridine (135 mg, 1.71 mmol) and DMAP (4.7 mg, 0.04
mmol). Then acetyl chloride (183 mg, 2.33 mmol) was added dropwise.
The mixture was stirred at room temperature for 16 h. The reaction
was diluted with water (30 mL), extracted with DCM (2.times.15 mL).
The extracts were washed with brine and dried (MgSO.sub.4).
Solvents were evaporated under reduced pressure. The residue was
purified by silica gel column, eluted with 30-50% ethyl acetate in
hexanes to give tert-butyl
2-(N-(4-(cyclopentanecarbonyl)-2-(methylthio)pyrimidin-5-yl)acetamido)ace-
tate (3b) as pale yellow oil (298 mg, 98%). MS-ESI (m/z): 394
[M+1].sup.+.
tert-Butyl
5-acetyl-7-cyclopentyl-7-hydroxy-2-(methylthio)-6,7-dihydro-5H--
pyrrolo[3,2-d]pyrimidine-6-carboxylate (3c)
To a solution of 3b (412 mg, 1.05 mmol) in DMF (8 mL) was added
K.sub.2CO.sub.3 (362 mg, 2.62 mmol). The mixture was heated at
60.degree. C. for 2 h. After cooling to room temperature, the
reaction was diluted with water and extracted with ethyl acetate
(2.times.20 mL). The extracts were washed with brine and dried
(MgSO.sub.4). Solvents were evaporated under reduced pressure to
give crude tert-butyl
5-acetyl-7-cyclopentyl-7-hydroxy-2-(methylthio)-6,7-dihydro-5H-pyrrolo[3,-
2-d]pyrimidine-6-carboxylate (3c) as yellow oil (412 mg, 100%).
MS-ESI (m/z): 394 [M+1].sup.+. This was carried on to next reaction
without further purification.
5-Acetyl-7-cyclopentyl-7-hydroxy-2-(methylthio)-6,7-dihydro-5H-pyrrolo[3,2-
-d]pyrimidine-6-carboxylic acid (3d)
To a solution of 3c (412 mg, 1.05 mmol) in DCM (2 mL) was added TFA
(5 mL). The mixture was stirred at room temperature for 2 h.
Solvents were evaporated under reduced pressure to give
5-acetyl-7-cyclopentyl-7-hydroxy-2-(methylthio)-6,7-dihydro-5H-pyrrolo[3,-
2-d]pyrimidine-6-carboxylic acid (3d) as yellow oil (353 mg, 100%).
MS-ESI (m/z): 338[M+1].sup.+. This was carried on to next reaction
without further purification.
5-Acetyl-7-cyclopentyl-7-hydroxy-N,N-dimethyl-2-(methylthio)-6,7-dihydro-5-
H-pyrrolo[3,2-d]pyrimidine-6-carboxamide (3e)
To a mixture of 3d (220 mg, 0.651 mmol), dimethylamine
hydrochloride (106 mg, 1.30 mmol), EDCI (187 mg, 0.977 mmol) and
HOBT hydrate (150 mg, 0.977 mmol) in anhydrous DMF (4 mL) was added
DIPEA (567 L, 3.26 mmol). The mixture was stirred at room
temperature for 17 h. The mixture was diluted with water and
extracted with ethyl acetate (2.times.). The extracts were washed
with brine and dried (Na.sub.2SO.sub.4). Solvents were evaporated
under reduced pressure. The residue was purified by silica gel
column, eluted with 50%-100% ethyl acetate in hexanes to give
5-acetyl-7-cyclopentyl-7-hydroxy-N,N-dimethyl-2-(methylthio)-6,7-dihydro--
5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide (3e) as white solid (127
mg, 54%). MS-ESI (m/z): 365 [M+1].sup.+.
5-Acetyl-7-cyclopentyl-7-hydroxy-N,N-dimethyl-2-(methylsulfonyl)-6,7-dihyd-
ro-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide (3f)
To a solution of 3e (169 mg, 0.465 mmol) in dichloromethane (10 mL)
at 0.degree. C. was added mCPBA (75%, 267 mg, 1.16 mmol). The
mixture was stirred at room temperature for 2 h. Saturated aqueous
NaHSO.sub.3 (3 mL) was added and stirred for 10 min. The mixture
was diluted with saturated aqueous NaHCO.sub.3 (20 mL) and
extracted with DCM (2.times.15 mL). The extracts were dried
(Na.sub.2SO.sub.4). Solvents were evaporated under reduced pressure
to give crude
5-acetyl-7-cyclopentyl-7-hydroxy-N,N-dimethyl-2-(methylsulfonyl)-6,7-dihy-
dro-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide (3f) as white solid
(184 mg, 100%). MS-ESI (m/z): 397 [M+1].sup.+.
tert-Butyl
4-(6-(5-acetyl-7-cyclopentyl-6-(dimethylcarbamoyl)-7-hydroxy-6,-
7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-ylamino)pyridin-3-yl)piperazine-1-c-
arboxylate (3g)
To a solution of tert-butyl
4-(6-formamidopyridin-3-yl)piperazine-1-carboxylate (69.0 mg, 0.225
mmol) in DMF (1 mL) at room temperature was added NaH (60%, 15 mg,
0.36 mmol). The mixture was stirred at room temperature for 20 min.
A solution of 3f (85.0 mg, 0.215 mmol) in DMF (1 mL) was added. The
mixture was stirred at room temperature for 1 h. Methanol (3 mL)
was added and stirred for 30 min. The mixture was diluted with
water (10 mL) and extracted with ethyl acetate (2.times.10 mL). The
extracts were dried (Na.sub.2SO.sub.4). Solvents were evaporated
under reduced pressure. The residue was purified by column on
silica gel, eluted with 50-100% EtOAc-hexanes and 5% methanol in
EtOAc to give tert-butyl
4-(6-(5-acetyl-7-cyclopentyl-6-(dimethylcarbamoyl)-7-hydroxy-6,7-dihydro--
5H-pyrrolo[3,2-d]pyrimidin-2-ylamino)pyridin-3-yl)piperazine-1-carboxylate
(3g) as white solid (39.0 mg, 30%). MS-ESI (m/z): 595
[M+1].sup.+.
7-Cyclopentyl-N,N-dimethyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)-5H-pyrr-
olo[3,2-d]pyrimidine-6-carboxamide (3)
A solution of 3g (14.3 mg) in 0.5 M H.sub.2SO.sub.4/methanol (1 mL)
was heated at 50.degree. C. for 16 h. The mixture was cooled to
room temperature. NaHCO.sub.3 (90 mg) was added and stirred for 10
min. Solvents were evaporated under reduced pressure. The residue
was purified by silica gel column, eluted with 94:5:1
DCM/methanol/ammonia to give
7-cyclopentyl-N,N-dimethyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)-5H-pyr-
rolo[3,2-d]pyrimidine-6-carboxamide (3) as pale yellow solid (3.0
mg, 29%). MS-ESI (m/z): 435 [M+1].sup.+.
Example 4
7-Cyclopentyl-N,N-dimethyl-2-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino-
)-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide (4)
##STR00013##
5-Acetyl-7-cyclopentyl-7-hydroxy-N,N-dimethyl-2-(5-(piperazin-1-yl)pyridin-
-2-ylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide
(4a)
To a solution of 3g (24.7 mg, 0.0416 mmol) in DCM (1 mL) was added
TFA (1.5 mL). The mixture was stirred at room temperature for 1.5
h. Solvents were evaporated under reduced pressure. The residue was
purified by silica gel column, eluted with 92:7:1
DCM-MeOH--NH.sub.3 (28%) to give
5-acetyl-7-cyclopentyl-7-hydroxy-N,N-dimethyl-2-(5-(piperazin-1-yl)pyridi-
n-2-ylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide
(4a) as pale yellow solid (7.0 mg, 34%). MS-ESI (m/z):
495[M+1].sup.+.
5-Acetyl-7-cyclopentyl-7-hydroxy-N,N-dimethyl-2-(5-(4-methylpiperazin-1-yl-
)
pyridin-2-ylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide
(4b)
To a solution of 4a (7.0 mg, 0.014 mmol) in 1,2-dichloroethane (0.3
mL) at room temperature was added formaldehyde (37% in water, 14
mg, 0.17 mmol) followed by NaBH(OAc).sub.3 (4.5 mg, 0.021 mmol).
The mixture was stirred at room temperature for 1 h. The mixture
was diluted with saturated aqueous NaHCO.sub.3 (5 mL) and extracted
with DCM (2.times.5 mL). The extracts were dried
(Na.sub.2SO.sub.4). Solvents were evaporated under reduced
pressure. The residue was purified by silica gel column, eluted
with 96:3:1 DCM/methanol/ammonia to give
5-acetyl-7-cyclopentyl-7-hydroxy-N,N-dimethyl-2-(5-(4-methylpiperazin-1-y-
l)
pyridin-2-ylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamid-
e (4b) as pale yellow solid (5.5 mg, 76%). MS-ESI (m/z): 509
[M+1].sup.+.
7-Cyclopentyl-N,N-dimethyl-2-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-
-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide (4)
A solution of 4b (5.5 mg) in 0.5 M H.sub.2SO.sub.4/methanol (1 mL)
was heated at 50.degree. C. for 14 h. The mixture was cooled to
room temperature. NaHCO.sub.3 (90 mg) was added and stirred for 10
min. Solvents were evaporated under reduced pressure. The residue
was purified by silica gel column, eluted with 94:5:1
DCM/methanol/ammonia to give
7-cyclopentyl-N,N-dimethyl-2-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino-
)-5H-pyrrolo[3, 2-d]pyrimidine-6-carboxamide (4) as pale yellow
solid (4.3 mg, 89%). MS-ESI (m/z): 449 [M+1].sup.+.
Example 5
7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrrol-
o[2,1-f][1,2,4]triazine-6-carboxamide (5)
##STR00014##
6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one (5a)
To the solution of pyruvic acid (18.4 g, 0.2 mol) in water (400 mL)
was added thiosemicarbazide (18.4 g, 0.2 mol) at room temperature,
then reaction mixture was heated to 70.degree. C. and stirred for 1
h. Reaction mixture was cooled to room temperature,
Na.sub.2CO.sub.3 (21.2 g, 0.2 mol) was carefully added to the above
mixture in several portions over 30 min, then reaction mixture was
heated to reflux for 3 h. Reaction mixture was cooled to room
temperature, acidified with acetic acid to pH 5. This suspension
was extracted with EtOAc (500 mL.times.2), EtOAc layer was washed
with water, brine, dried with anhydrous Na.sub.2SO.sub.4, filtered
and the solvent was removed, giving pale yellow solid
6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one (5a) (23.6
g). MS-ESI (m/z): 144 [M+1].sup.+.
6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (5b)
To the solution of 5a (23.6 g, 165 mmol) in 1N NaOH aq. (330 mL)
was added dropwise MeI (10.3 mL, 165 mmol) at room temperature,
then reaction mixture was stirred for 1 h, and acidified with
acetic acid to pH 5. This suspension was filtrated, washed with
water (500 mL.times.2), dried in vacuo to give the product
6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (5b) (14.5 g).
MS-ESI (m/z): 158 [M+1].sup.+.
5-chloro-6-methyl-3-(methylthio)-1,2,4-triazine (5c)
The mixture of 5b (14.5 g, 92 mmol) in POCl.sub.3 (120 mL) was
heated to reflux for 1 h, then reaction mixture was cooled to
50.degree. C., and concentrated in vacuo to 1/5 volume. The
resulting residue was diluted with DCM (500 mL), washed with cold
water (500 mL.times.5), brine (500 mL.times.2), dried with
anhydrous Na.sub.2SO.sub.4, filtered and the solvent was removed,
giving black residue
5-chloro-6-methyl-3-(methylthio)-1,2,4-triazine (5c) (9.6 g).
MS-ESI (m/z): 176 [M+1].sup.+.
6-methyl-3-(methylthio)-1,2,4-triazine (5d)
To the ice-water cooled suspension of 5c (9.6 g, 55 mmol) in i-PrOH
(210 mL) was added NaBH.sub.4 (10.5g, 275 mmol) in several
portions, then the reaction mixture was stirred at 0-5.degree. C.
for 1 h. The mixture was filtrated, washed with cooled i-PrOH (20
mL). The filtrate was concentrated in vacuo. To the crude product
was added DCM (300 mL) and DDQ (12.5 g, 55 mmol), the mixture was
stirred at room temperature for 16 h, filtrated, filtrate was
concentrated in vacuo and purified through flash column
chromatography (eluent: petro ether/ethyl acetate=50:1.fwdarw.10:1)
to give 6-methyl-3-(methylthio)-1,2,4-triazine (5d) (2.3 g). MS-ESI
(m/z): 142 [M+1].sup.+.
6-(bromomethyl)-3-(methylthio)-1,2,4-triazine (5e)
To the solution of 5d (2.3 g, 16.3 mmol) in CCl.sub.4 (80 mL) was
added NBS (3.2 g, 17.9 mmol), and BPO (395 mg, 1.63 mmol). This
mixture was heated to reflux for 1 h and cooled to room
temperature, additional NBS (3.2 g, 17.9 mmol), and BPO (395 mg,
1.63 mmol) was added to the above mixture. This resulting mixture
was heated to reflux again for 1 h. After cooled to room
temperature, the mixture was filtrated, washed with DCM (20 mL).
Filtrate was combined, washed with sat. Na.sub.2SO.sub.3 aq. brine,
dried with anhydrous Na.sub.2SO.sub.4, filtered and the filtrate
was concentrated in vacuo and purified through flash column
chromatography (eluent: petro ether/ethyl acetate=50:1.fwdarw.25:1)
to give 6-(bromomethyl)-3-(methylthio)-1,2,4-triazine (5e) (0.88
g). MS-ESI (m/z): 220, 222 [M+1].sup.+.
ethyl
3-cyclopentyl-2-((3-(methylthio)-1,2,4-triazin-6-yl)methyl)-3-oxopro-
panoate (5f)
To the ice-water cooled solution of ethyl
3-cyclopentyl-3-oxopropanoate (1.47 g, 8.0 mmol) in DMF (8.0 mL)
was added 60% NaH (160 mg, 4.0 mmol), after stirring for 10 min at
room temperature, the mixture was recooled to 0-5.degree. C., the
solution of 5e (0.88 g, 4.0 mmol) in DMF (4.0 mL) was added to the
above solution, then reaction mixture was slowly warmed to room
temperature and stirred for 1 h, quenched with sat. NH4Cl aq.,
extracted with EtOAc. Organic layer was washed with water and
brine, dried with anhydrous Na.sub.2SO.sub.4, filtered and the
filtrate was concentrated in vacuo and purified through flash
column chromatography (eluent: petro ether/ethyl
acetate=50:1.fwdarw.10:1) to give ethyl
3-cyclopentyl-2-((3-(methylthio)-1,2,4-triazin-6-yl)methyl)-3-oxopropanoa-
te (5f) (0.75 g). MS-ESI (m/z): 324 [M+1].sup.+.
ethyl
7-cyclopentyl-2-(methylthio)pyrrolo[2,1-f][1,2,4]triazine-6-carboxyl-
ate (5g)
The mixture of 5f (0.75 g, 2.3 mmol) in POCl.sub.3 (23 mL) was
heated to reflux for 16 h. Then reaction mixture cooled to
50.degree. C. and concentrated in vacuo, this crude product ethyl
7-cyclopentyl-2-(methylthio)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate
(5g) was used in next step without further purification. MS-ESI
(m/z): 306 [M+1].sup.+.
7-cyclopentyl-2-(methylthio)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic
acid (5h)
To the mixture of 5g (700 mg, 2.3 mmol) in THF/MeOH/H.sub.2O (36
mL, v:v:v=1:1:1) was added LiOH.H.sub.2O (1.45 g, 34.5 mmol), this
mixture was stirred at room temperature for 16 h, acidified with 1
N HCl aq. to pH 2-3, extracted with EtOAc, the organic layer was
washed with water, brine, dried with anhydrous Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The residue
7-cyclopentyl-2-(methylthio)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic
acid (5h) was used in next step without further purification.
MS-ESI (m/z): 278 [M+1].sup.+.
7-cyclopentyl-N,N-dimethyl-2-(methylthio)pyrrolo[2,1-f][1,2,4]triazine-6-c-
arboxamide (5i)
The mixture of 5h (554 mg, 2.0 mmol), HOBT (540 mg, 4.0 mmol), EDCI
(575 mg, 3.0 mmol), dimethylamine hydrochloride (489 mg, 6.0 mmol),
Et.sub.3N (1.39 mL, 10.0 mmol) and MS4 .ANG. (2.0 g) in DMF (20 mL)
was stirred at room temperature for 16 h. The mixture was extracted
with water and EtOAc, organic layer was washed with water, brine,
dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue
7-cyclopentyl-N,N-dimethyl-2-(methylthio)pyrrolo[2,
1-f][1,2,4]triazine-6-carboxamide (5i) was used in next step
without further purification. MS-ESI (m/z): 305 [M+1].sup.+.
7-cyclopentyl-N,N-dimethyl-2-(methylsulfinyl)pyrrolo[2,1-][1,2,4]triazine--
6-carboxamide (5j)
To the solution of 5i (630 mg, 2.0 mmol) in DCM (20 mL) was added
m-CPBA (460 mg, 2.0 mmol), reaction mixture was stirred at ambient
temperature for 1 h. The mixture was quenched with sat. NaHCO.sub.3
aq., DCM layer was washed with water, brine, dried with anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
7-cyclopentyl-N,N-dimethyl-2-(methyl
sulfinyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide (5j) was used
in next step without further purification. MS-ESI (m/z): 321
[M+1].sup.+.
7-cyclopentyl-2-((4-methoxybenzyl)amino)-N,N-dimethylpyrrolo[2,1-f][1,2,4]-
triazine-6-carboxamide (5k)
To the solution of 5j (665 mg, 2.0 mmol) in NMP (20 mL) was added
PMBNH.sub.2 (1.30 mL, 10.0 mmol), reaction mixture was heated to
80.degree. C. and stirred for 16 h. The mixture was cooled to
ambient temperature and extracted with water and EtOAc, organic
layer was washed with water, brine, dried with anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
7-cyclopentyl-2-((4-methoxybenzyl)amino)-N,N-dimethylpyrrolo
[2,1-f][1,2,4]triazine-6-carboxamide (5k) was used in next step
without further purification. MS-ESI (m/z): 394 [M+1].sup.+.
2-amino-7-cyclopentyl-N,N-dimethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxam-
ide (5l)
To the solution of 5k (.apprxeq.500 mg, 1.0 mmol) in DCM (10 mL)
was added dropwise TFA (10 mL), reaction mixture was stirred at
ambient temperature for 5 h. The mixture was concentrated in vacuo
and basified with ammonia to pH 9-10, concentrated in vacuo. The
residue was purified through flash column chromatography (eluent:
DCM/Methanol=100:1.fwdarw.10:1) to give
2-amino-7-cyclopentyl-N,N-dimethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxa-
mide (5l) (136 mg). MS-ESI (m/z): 274 [M+1].sup.+.
tert-butyl
4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,1-f][1,2,4]-
triazin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (5m)
The mixture of 5l (10 mg, 0.03663 mmol), tert-butyl
4-(6-chloropyridin-3-yl) piperazine-1-carboxylate (22 mg, 0.07326
mmol), Pd.sub.2dba.sub.3 (12.8 mg, 0.01832 mmol), Xphos (21.2 mg,
0.03663 mmol), and .sup.tBuONa (10.5 mg, 0.11 mmol) in 1,4-dioxane
(0.72 mL) was heated to 105.degree. C. and stirred under N.sub.2
for 16 h. Then mixture was cooled to room temperature and diluted
with EtOAc, filtered through a pad of celite, filtrate was
concentrated in vacuo and purified through flash column
chromatography (eluent: DCM/Methanol=100:1.fwdarw.10:1) to give
tert-butyl
4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,1-f][1,2,4]triazin-2--
yl)amino) pyridin-3-yl)piperazine-1-carboxylate (5m) (7.0 mg).
MS-ESI (m/z): 535 [M+1].sup.+.
7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrrol-
o[2,1-f][1,2,4]triazine-6-carboxamide (5)
The mixture of 5m (7.0 mg, 0.0131 mmol) in 4N HCl/EtOAc (1 mL) was
stirred for 3 h. Then mixture was concentrated in vacuo and
basified with ammonia to pH 9-10, concentrated in vacuo again,
purified through flash column chromatography (eluent:
DCM/Methanol=10:1) to give
7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridine-2-yl)amino)pyrr-
olo[2,1-f][1,2,4]triazine-6-carboxamide (5) (4.6 mg). MS-ESI (m/z):
435 [M+1].sup.+.
Example 6
7-cyclopentyl-N,N-dimethyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amin-
o) pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide (6)
##STR00015##
The mixture of 5l (11 mg, 0.040 mmol),
1-(6-chloropyridin-3-yl)-4-methylpiperazine (15 mg, 0.071 mmol),
Pd.sub.2dba.sub.3 (7.0 mg, 0.010 mmol), Xphos (11.6 mg, 0.020
mmol), and .sup.tBuONa (19.2 mg, 0.20 mmol) in 1,4-dioxane (1.2 mL)
was heated to 105.degree. C. and stirred under N.sub.2 for 16 h.
Then mixture was cooled to room temperature and diluted with EtOAc,
filtered through a pad of celite, filtrate was concentrated in
vacuo and purified through flash column chromatography (eluent:
DCM/Methanol=10:1) to give
7-cyclopentyl-N,N-dimethyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)ami-
no)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide (6) (5.0 mg). MS-ESI
(m/z): 449 [M+1].sup.+.
Example 7
7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)furo[3-
,2-d]pyrimidine-6-carboxamide (7)
##STR00016##
5-bromo-4-(((tert-butyldimethylsilyl)oxy)(cyclopentyl)methyl)-2-(methylthi-
o)pyrimidine (7a)
To a solution of 1a (1.6 g, 5.28 mmol) in MeCN (26 mL) was added
DBU (4.74 mL, 31.7 mmol), and TBSCl (3.98 g, 26.4 mmol) at
0-5.degree. C. under N.sub.2. The reaction mixture was slowly
warmed to ambient temperature and stirred for 5 h, then diluted
with EtOAc (50 mL), washed with 1N HCl aq. (20 mL), water (25 mL),
sat. NaHCO.sub.3 aq. (20 mL), brine, and dried with anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified through flash column chromatography (eluent:
hexane/ethyl acetate=100:1) to give
5-bromo-4-(((tert-butyldimethylsilyl)oxy)(cyclopentyl)methyl)-2-(methylth-
io)pyrimidine (7a) (2.2 g). MS-ESI (m/z): 417, 419 [M+1].sup.+.
(4-(((tert-butyldimethylsilyl)oxy)(cyclopentyl)methyl)-2-(methylthio)pyrim-
idin-5-yl)boronic acid (7b)
To the cooled solution of 7a (2.2 g, 5.2 mmol) in dry THF (52 mL)
was added B(OMe).sub.3 (4.0 mL, 36 mmol) and n-BuLi (2.5 M in
hexane, 12 mL) at -78.degree. C. under N.sub.2. The reaction
mixture was slowly warmed to 0.degree. C. over 2 h, and then
quenched with 3N HCl aq. (13 mL), extracted with EtOAc (50 mL),
washed with brine, and dried with anhydrous Na.sub.2SO.sub.4,
filtered and concentrated in vacuo to give colorless residue
(4-(((tert-butyldimethylsilyl)oxy)
(cyclopentyl)methyl)-2-(methylthio)pyrimidin-5-yl)boronic acid
(7b), used in next step without further purification. MS-ESI (m/z):
383 [M+1].sup.+.
4-(((tert-butyldimethylsilyl)oxy)(cyclopentyl)methyl)-2-(methylthio)pyrimi-
din-5-ol (7c)
To the mixture of 7b (crude product, 5.2 mmol) in THF/H.sub.2O (60
mL, v:v=1:1) was added NaBO.sub.3.4H.sub.2O (2.3 g, 15 mmol) in
several portions at 0-5.degree. C., then reaction mixture was
warmed to ambient temperature and stirred for 5 h, quenched with 1N
HCl to pH2-3, extracted with EtOAc, washed with water, brine, dried
with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was purified through flash column chromatography
(eluent: hexane/ethyl acetate=20:1) to give
4-(((tert-butyldimethylsilyl)oxy)(cyclopentyl)methyl)-2-(methylthio)pyrim-
idin-5-ol (7c) (1.6 g). MS-ESI (m/z): 355 [M+1].sup.+.
ethyl
2-((4-(((tert-butyldimethylsilyl)oxy)(cyclopentyl)methyl)-2-(methylt-
hio) pyrimidin-5-yl)oxy)acetate (7d)
To the solution of 7c (1.6 g, 4.5 mmol) and ethyl 2-bromoacetate
(0.5 mL, 4.5 mmol) in DMF (23 mL) was added Cs.sub.2CO.sub.3 (2.2
g, 6.8 mmol) at ambient temperature, then reaction mixture was
stirred for 1 h, quenched with sat. NH.sub.4Cl aq., extracted with
EtOAc, washed with water, brine, dried with anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give
residue ethyl
2-((4-(((tert-butyldimethylsilyl)oxy)(cyclopentyl)methyl)-2-(methylthio)
pyrimidin-5-yl)oxy)acetate (7d). This residue was used in next step
without further purification. MS-ESI (m/z): 441 [M+1].sup.+.
ethyl
2-((4-(cyclopentyl(hydroxy)methyl)-2-(methylthio)pyrimidin-5-yl)oxy)
acetate (7e)
To the ice-water cooled solution of 7d (crude product, 4.5 mmol) in
MeCN (45 mL) was added BF.sub.3.Et.sub.2O (3.0 mL) under N.sub.2.
Then reaction mixture was warmed to ambient temperature and stirred
for 30 min, quenched with sat. NaHCO.sub.3 aq. to pH 8-9, extracted
with EtOAc, washed with water, brine, dried with anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give ethyl
2-((4-(cyclopentyl(hydroxy)methyl)-2-(methylthio)pyrimidin-5-yl)oxy)
acetate (7e) (1.1 g). MS-ESI (m/z): 327 [M+1].sup.+.
ethyl
2-((4-(cyclopentanecarbonyl)-2-(methylthio)pyrimidin-5-yl)oxy)acetat-
e (7f)
To the ice-water cooled solution of 7e (490 mg, 1.5 mmol) in DCM
(20 mL) was added Dess-Martin periodinane (1.28 g, 3.0 mmol), the
reaction mixture was warmed to room temperature and stirred for 1
h, quenched with sat. NaHCO.sub.3 aq. (10 mL), washed with brine,
and dried with anhydrous Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue was purified through flash
column chromatography (eluent: hexane/ethyl acetate=20:1) to give
ethyl
2-((4-(cyclopentanecarbonyl)-2-(methylthio)pyrimidin-5-yl)oxy)acetate
(7f) (320 mg). MS-ESI (m/z): 325 [M+1].sup.+.
7-cyclopentyl-2-(methylthio)furo[3,2-d]pyrimidine-6-carboxylic acid
(7g)
To the ice-water cooled solution of 7f (290 mg, 0.9 mmol) in THF
(11 mL) was added 60% NaH (125 mg, 3.2 mmol), the reaction mixture
was slowly warmed to room temperature and stirred for 30 min,
quenched with 1N HCl aq. to pH 2-3, extracted with EtOAc, washed
with brine, and dried with anhydrous Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to give
7-cyclopentyl-2-(methylthio)furo[3,2-d]pyrimidine-6-carboxylic acid
(7g). MS-ESI (m/z): 279 [M+1].sup.+.
7-cyclopentyl-N,N-dimethyl-2-(methylthio)furo[3,2-d]pyrimidine-6-carboxami-
de (7h)
The mixture of 7g (crude product, 0.90 mmol), HOBT (243 mg, 1.59
mmol), EDCI (228 mg, 1.19 mmol), dimethylamine hydrochloride (194
mg, 2.38 mmol), and DIPEA (0.65 mL, 3.97 mmol) in DMF (16 mL) was
stirred at ambient temperature for 16 h, quenched with 1N HCl to
pH2-3, extracted with EtOAc, washed with water, brine, dried with
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
give
7-cyclopentyl-N,N-dimethyl-2-(methylthio)furo[3,2-d]pyrimidine-6-carboxam-
ide (7h). MS-ESI (m/z): 306 [M+1].sup.+.
7-cyclopentyl-N,N-dimethyl-2-(methylsulfonyl)furo[3,2-d]pyrimidine-6-carbo-
xamide (7i)
To the solution of 7h (crude product) in DCM (16 mL) was added
m-CPBA (355 mg, 1.59 mmol), reaction mixture was stirred at ambient
temperature for 1 h, quenched with sat. NaHCO.sub.3 aq. DCM layer
was washed with water, brine, dried with anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified through flash column chromatography (eluent:
hexane/acetone=2:1) to give
7-cyclopentyl-N,N-dimethyl-2-(methylsulfonyl)furo[3,2-d]pyrimidine-6-carb-
oxamide (7i) (69 mg). MS-ESI (m/z): 338 [M+1].sup.+.
tert-butyl
4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)furo[3,2-d]pyrimidin--
2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (7j)
To the ice-water cooled solution of 7i (33.7 mg, 0.1 mmol) and
tert-butyl 4-(6-formamidopyridin-3-yl)piperazine-1-carboxylate
(30.6 mg, 0.1 mmol) in DMF (2 mL) was added 60% NaH (8.0 mg, 0.2
mmol), the reaction mixture was slowly warmed to room temperature
and stirred for 2 h, quenched with sat. NH.sub.4Cl aq., extracted
with EtOAc, washed with brine, and dried with anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified through flash column chromatography (eluent:
DCM/Methanol=50:1) to give tert-butyl
4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)furo[3,2-d]pyrimidin-2-yl)amino-
) pyridine-3-yl)piperazine-1-carboxylate (7j) (5.3 mg). MS-ESI
(m/z): 536 [M+1].sup.+.
7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)furo[3-
,2-d]pyrimidine-6-carboxamide (7)
##STR00017##
To the solution of 7j (5.3 mg, 0.01 mmol) in DCM (0.5 mL) was added
TFA (0.5 mL) at ambient temperature. This mixture was stirred for
40 min, and concentrated in vacuo, basified with ammonia to pH 9-10
and concentrated in vacuo again. The residue was purified through
flash column chromatography (eluent: DCM/MeOH=10:1) to give
7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)furo[-
3,2-d]pyrimidine-6-carboxamide (7) (2.8 mg). MS-ESI (m/z): 436
[M+1].sup.+.
Example 8
7-cyclopentyl-N,N-dimethyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amin-
o) furo[3,2-d]pyrimidine-6-carboxamide (8)
##STR00018##
To the ice-water cooled solution of 7i (33.7 mg, 0.1 mmol) and
N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)formamide (22.0 mg, 0.1
mmol) in DMF (2 mL) was added 60% NaH (8.0 mg, 0.2 mmol), the
reaction mixture was slowly warmed to room temperature and stirred
for 2 h, quenched with sat. NH.sub.4Cl aq., extracted with EtOAc,
washed with brine, and dried with anhydrous Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The residue was purified
through flash column chromatography (eluent: DCM/Methanol=10:1) to
give
7-cyclopentyl-N,N-dimethyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)ami-
no)furo[3,2-d]pyrimidine-6-carboxamide (8) (2.4 mg). MS-ESI (m/z):
450 [M+1].sup.+.
Example 9
7-Cyclopentyl-N,N,5-trimethyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)-5H-p-
yrrolo[3,2-d]pyrimidine-6-carboxamide (9)
##STR00019##
tert-Butyl
4-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-5H-pyrrolo[3,2-d]pyri-
midin-2-ylamino)pyridin-3-yl)piperazine-1-carboxylate (9a)
To a solution of 3 (11.2 mg) in DCM (0.5 mL) was added Boc.sub.2O
(6.1 mg) followed by TEA (5.4 .mu.L). The mixture was stirred at
room temperature for 2 h. Solvents were evaporated under reduced
pressure. The residue was purified by silica gel column, eluted
with 95:5 DCM/methanol to give tert-Butyl
4-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-5H-pyrrolo[3,2-d]pyrimidin-2-yl-
amino)pyridin-3-yl)piperazine-1-carboxylate (9a) as pale yellow
solid (12.0 mg, 87%). MS-ESI (m/z): 535.5 [M+1].sup.+.
tert-Butyl
4-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-5-methyl-5H-pyrrolo[3-
,2-d]pyrimidin-2-ylamino)pyridin-3-yl)piperazine-1-carboxylate
(9b)
To a solution of 9a (12.0 mg, 0.0225 mmol) in THF (0.5 mL) was NaH
(60%, 2.0 mg, 0.050 mmol). After stirring at rt for 10 min., a
solution of MeI (3.2 mg, 0.0225 mmol) in THF (0.25 mL) was added.
The mixture was stirred at room temperature for 2.5 h. Solvents
were evaporated under reduced pressure. The residue was purified by
silica gel column, eluted with 3% MeOH in DCM and then with 92:7:1
DCM-MeOH--NH.sub.3 (28%) to give tert-Butyl
4-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-5-methyl-5H-pyrrolo[3,2-d]pyrim-
idin-2-ylamino) pyridin-3-yl)piperazine-1-carboxylate (9b) as pale
yellow solid (7.9 mg, 64%). MS-ESI (m/z): 549.5 [M+1].sup.+.
7-Cyclopentyl-N,N,5-trimethyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)-5H-p-
yrrolo[3,2-d]pyrimidine-6-carboxamide (9)
To a solution of 9b (7.8 mg) in DCM (0.5 mL) was added TFA (0.5
mL). The mixture was stirred at room temperature for 1 h. Solvents
were evaporated under reduced pressure. The residue was purified by
silica gel column, eluted with 91:8:1 DCM-MeOH--NH.sub.3 (28%) to
give
7-Cyclopentyl-N,N,5-trimethyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)-5H--
pyrrolo[3,2-d]pyrimidine-6-carboxamide (9) as pale yellow solid
(6.4 mg, 100%). MS-ESI (m/z): 449.4[M+1].sup.+.
Example 10
7-Cyclopentyl-N,N,
5-trimethyl-2-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-5H-pyrrolo[3,-
2-d]pyrimidine-6-carboxamide (10)
##STR00020##
To a solution of 9 (3.9 mg, 0.0087 mmol) in 1,2-dichloroethane (0.3
mL) at room temperature was added formaldehyde (37% in water, 9.2
mg, 0.11 mmol) followed by NaBH(OAc).sub.3 (2.4 mg, 0.011 mmol).
The mixture was stirred at room temperature for 1 h. The mixture
was diluted with saturated aqueous NaHCO.sub.3 (1 mL) and extracted
with DCM (2.times.1 mL). The extracts were dried
(Na.sub.2SO.sub.4). Solvents were evaporated under reduced
pressure. The residue was purified by silica gel column, eluted
with 95:4:1 DCM/methanol/ammonia to give
7-cyclopentyl-N,N,5-trimethyl-2-(5-(4-methylpiperazin-1-yl)pyridin-2-ylam-
ino)-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide (10) as pale yellow
solid (2.6 mg, 65%). MS-ESI (m/z): 463.4 [M+1].sup.+.
Following essentially the same procedures described for Examples 1,
Examples 11-64 listed in Table 1 were prepared by replacing
tert-butyl 4-(6-formamidopyridin-3-yl)piperazine-1-carboxylate with
the corresponding aminopyridines or aminopyridazines and sequential
modifications as necessary, such as acylation and reductive
amination, or using similar synthetic strategies or methods. The
structures and names of Examples 11-64 are given in Table 1.
TABLE-US-00001 TABLE 1 EXAMPLE STRUCTURE NAME DATA 11 ##STR00021##
(S)-7-cyclopentyl-N,N-dimethyl-2-((5-(3-oxotetrahy-
dro-3H-oxazolo[3,4-a]pyrazin-7(1H)-yl)pyridin-2-yl)
amino)thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 508 [M +
1].sup.+ 12 ##STR00022##
(R)-7-cyclopentyl-N,N-dimethyl-2-((5-(3-oxotetrahy-
dro-3H-oxazolo[3,4-a]pyrazin-7(1H)-yl)pyridin-2-yl)
amino)thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 508 [M +
1].sup.+ 13 ##STR00023##
(R)-7-cyclopentyl-N,N-dimethyl-2-((5-(morpholin-2-
yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-car- boxamide
MS-ESI (m/z): 453 [M + 1].sup.+ 14 ##STR00024##
2-((5-(4-aminopiperidin-1-yl)pyridin-2-yl)amino)-7-
cyclopentyl-N,N-dimethylthieno[3,2-d]pyrimidine-6- carboxamide
MS-ES (m/z): 466 [M + 1].sup.+ 15 ##STR00025##
7-cyclopentyl-N,N-dimethyl-2-((5-(4-(methylamino)
piperidin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyri-
midine-6-carboxamide MS-ESI (m/z): 480 [M + 1].sup.+ 16
##STR00026## 7-cyclopentyl-2-((5-(4-(dimethylamino)piperidin-1-
yl)pyridin-2-yl)amino)-N,N-dimethylthieno[3,2-d]py-
rimidine-6-carboxamide MS-ESI (m/z): 494 [M + ].sup.+ 17
##STR00027## (S)-7-cyclopentyl-2-((5-(3-(methoxymethyl)piperazin-
1-yl)pyridin-2-yl)amino)-N,N-dimethylthieno[3,2-
d]pyrimidine-6-carboxamide MS-ESI (m/z): 496 [M + 1].sup.+ 18
##STR00028## (S)-7-cyclopentyl-2-((5-(3-(methoxymethyl)-4-meth-
ylpiperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-
thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 510 [M +
1].sup.+ 19 ##STR00029##
(S)-7-cyclopentyl-2-((5-(4-ethyl-3-(methoxymethyl)
piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-
thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 524 [M +
H].sup.+ 20 ##STR00030##
(S)-7-cyclopentyl-2-((5-(3-(hydroxymethyl)piperazin-
1-yl)pyridin-2-yl)amino)-N,N-dimethylthieno[3,2-
d]pyrimidine-6-carboxamide MS-ESI (m/z): 482 [M + 1].sup.+ 21
##STR00031## (S)-7-cyclopentyl-2-((5-(3-(hydroxymethyl)-4-meth-
ylpiperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-
thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 496 [M +
1].sup.+ 22 ##STR00032##
(S)-7-cyclopentyl-2-((5-(4-ethyl-3-(hydroxymethyl)
piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-
thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 510 [M +
1].sup.+ 23 ##STR00033##
(R)-7-cyclopentyl-2-((5-(3-(methoxymethyl)piperazin-
1-yl)pyridin-2-yl)amino)N,N-dimethylthieno[3,2-
d]pyrimidine-6-carboxamide MS-ESI (m/z): 496 [M + 1].sup.+ 24
##STR00034## (R)-7-cyclopentyl-2-((5-(3-(methoxymethyl)-4-meth-
ylpiperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-
thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 510 [M +
1].sup.+ 25 ##STR00035##
(R)-7-cyclopentyl-2-((5-(4-ethyl-3-(methoxymethyl)
piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-
thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 524 [M +
1].sup.+ 26 ##STR00036##
(R)-7-cyclopentyl-2-((5-(3-(hydroxymethyl)piperazin-
1-yl)pyridin-2-yl)amino)-N,N-dimethylthieno[3,2-
d]pyrimidine-6-carboxamide MS-ESI (m/z): 482 [M + 1].sup.+ 27
##STR00037## (R)-7-cyclopentyl-2-((5-(3-(hydroxymethyl)-4-meth-
ylpiperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-
thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 496 [M +
1].sup.+ 28 ##STR00038##
(R)-7-cyclopentyl-2-((5-(4-ethyl-3-(hydroxymethyl)
piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethyl-
thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 510 [M +
1].sup.+ 29 ##STR00039##
7-cyclopentyl-N,N-dimethyl-2-((5-(piperidin-4-yl)py-
ridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carbox- amide MS-ESI
(m/z): 451 [M + 1].sup.+ 30 ##STR00040##
7-cyclopentyl-N,N-dimethyl-2-((5-(1-methylpiperidin-
4-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6- carboxamide
MS-ESI (m/z): 465 [M + 1].sup.+ 31 ##STR00041##
2-((5-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)pyri-
din-2-yl)amino)-7-cyclopentyl-N,N-dimethylthieno
[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 464 [M + 1].sup.+ 32
##STR00042## 7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl-
methyl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine- 6-carboxamide
MS-ESI (m/z): 466 [M + 1].sup.+ 33 ##STR00043##
7-cyclopentyl-N,N-dimethyl-2-((5-((4-methylpiperazin-
1-yl)methyl)pyridin-2-yl)amino)thieno[3,2-d]
pyrimidine-6-carboxamide MS-ESI (m/z): 480 [M + 1].sup.+ 34
##STR00044## 7-cyclopentyl-2-((5-((4-ethylpiperazin-1-yl)methyl)
pyridin-2-yl)amino)-N,N-dimethylthieno[3,2-d]
pyrimidine-6-carboxamide MS-ESI (m/z): 494 [M + 1].sup.+ 35
##STR00045## 2-((5-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)py-
ridin-2-yl)amino)-7-cyclopentyl-N,N-dimethylthieno
[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 464 [M + 1].sup.+ 36
##STR00046## 7-cyclopentyl-N,N-dimethyl-2-((5-((1S,4S)-5-methyl-
2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)
amino)thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 478 [M +
1].sup.+ 37 ##STR00047##
(R)-7-cyclopentyl-2-((5-(hexahydropyrrolo[1,2-a]py-
razin-2(1H)-yl)pyridin-2-yl)amino)-N,N-dimethyl-
thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 492 [M +
1].sup.+ 38 ##STR00048##
(S)-7-cyclopentyl-2-((5-(hexahydropyrrolo[1,2-a]pyra-
zin-2(1H)-yl)pyridin-2-yl)amino)-N,N-dimethyl-
thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 492 [M +
1].sup.+ 39 ##STR00049##
2-((5-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)
pyridin-2-yl)amino)-7-cyclopentyl-N,N-dimethyl-
thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 464 [M +
1].sup.+ 40 ##STR00050##
2-((5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-2-
yl)amino)-7-cyclopentyl-N,N-dimethylthieno[3,2-d]
pyrimidine-6-carboxamide MS-ESI (m/z): 464 [M + 1].sup.+ 41
##STR00051## 7-cyclopentyl-N,N-dimethyl-2-((5-(6-methyl-3,6-diaza-
bicyclo[3.1.1]heptan-3-yl)pyridin-2-yl)amino)
thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 478 [M +
1].sup.+ 42 ##STR00052##
7-cyclopentyl-2-((5-(6-ethyl-3,6-diazabicyclo[3.1.1]
heptan-3-yl)pyridin-2-yl)amino)-N,N-dimethylthieno
[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 492 [M + 1].sup.+ 43
##STR00053## 7-cyclopentyl-2-((5-((7R,8aR)-7-hydroxyhexahydro
pyrrolo[1,2-a]pyrazin-2(1H-yl)pyridin-2-yl)amino)-
N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 508
[M + 1].sup.+ 44 ##STR00054##
7-cyclopentyl-2-((5-((7S,8aR)-7-hydroxyhexahydro-
pyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-2-yl)amino)-
N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 508
[M + 1].sup.+ 45 ##STR00055##
7-cyclopentyl-2-((5-((7R,8aS)-7-hydroxyhexahydro-
pyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-2-yl)amino)-
N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 508
[M + 1].sup.+ 46 ##STR00056##
2-((5-(3,6-diazabicyclo[3.2.0]heptan-3-yl)pyridin-2-
yl)amino)-7-cyclopentyl-N,N-dimethylthieno[3,2-d]
pyrimidine-6-carboxamide MS-ESI (m/z): 464 [M + 1].sup.+ 47
##STR00057## 7-cyclopentyl-N,N-dimethyl-2-((5-(6-methyl-3,6-diaza-
bicyclo[3.2.0]heptan-3-yl)pyridin-2-yl)amino)
thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 478 [M +
1].sup.+ 48 ##STR00058##
7-cyclopentyl-2-((5-(6-ethyl-3,6-diazabicyclo[3.2.0]
heptan-3-yl)pyridin-2-yl)amino)-N,N-dimethylthieno
[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 491 [M + 1].sup.+ 49
##STR00059## 7-cyclopentyl-N,N-dimethyl-2-((6-(piperazin-1-yl)
pyridazin-3-yl)amino)thieno[3,2-d]pyrimidine-6- carboxamide MS-ESI
(m/z): 453 [M + 1].sup.+ 50 ##STR00060##
7-cyclopentyl-N,N-dimethyl-2-((6-(4-methylpiperazin-
1-yl)pyridazin-3-yl)amino)thieno[3,2-d]pyrimidine- 6-carboxamide
MS-ESI (m/z): 467 [M + 1].sup.+ 51 ##STR00061##
2-((6-(4-acetylpiperazin-1-yl)pyridazin-3-yl)amino)-
7-cyclopentyl-N,N-dimethylthieno[3,2-d]pyrimidine- 6-carboxamide
MS-ESI (m/z): 495 [M + 1].sup.+ 52 ##STR00062##
7-cyclopentyl-2-((6-(4-(2-hydroxyacetyl)piperazin-1-
yl)pyridazin-3-yl)amino)-N,N-dimethylthieno[3,2-d]
pyrimidine-6-carboxamide MS-ESI (m/z): 511 [M + 1].sup.+ 53
##STR00063## 7-cyclopentyl-N,N-dimethyl-2-((6-(4-(2-(methyl-
sulfonyl)ethyl)piperazin-1-yl)pyridazin-3-yl)amino)
thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 559 [M +
1].sup.+ 54 ##STR00064##
7-cyclopentyl-N,N-dimethyl-2-((5,6,7,8-tetrahydro-
1,6-naphthyridin-2-yl)amino)thieno[3,2-d] pyrimidine-6-carboxamide
MS-ESI (m/z): 423 [M + 1].sup.+ 55 ##STR00065##
7-cyclopentyl-N,N-dimethyl-2-((6-methyl-5,6,7,8-
tetrahydro-1,6-naphthyridin-2-yl)amino)thieno
[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 437 [M + 1].sup.+ 56
##STR00066## 7-cyclopentyl-2-((5-(4-(2-hydroxyethyl)piperazin-1-
yl)pyridin-2-yl)amino)-N,N-dimethylthieno[3,2-d]
pyrimidine-6-carboxamide MS-ESI (m/z): 496 [M + 1].sup.+ 57
##STR00067## 7-cyclopentyl-2-((5-(4-(2-methoxyethyl)piperazin-1-
yl)pyridin-2-yl)amino)-N,N-dimethylthieno[3,2-d]
pyrimidine-6-carboxamide MS-ESI (m/z): 510 [M + 1].sup.+ 58
##STR00068## 7-cyclopentyl-N,N-dimethyl-2-((5-(4-(2-(methyl-
sulfonyl)ethyl)piperazin-1-yl)pyridin-2-yl)amino)
thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 558 [M +
1].sup.+ 59 ##STR00069##
7-cyclopentyl-2-((5-(4-ethylpiperazin-1-yl)pyridin-2-
yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6- carboxamide MS-ESI
(m/z): 480 [M + 1].sup.+ 60 ##STR00070##
7-cyclopentyl-2-((5-((3S,5R)-3,5-dimethylpiperazin-
1-yl)pyridin-2-yl)amino)-N,N-dimethylthieno[3,2-d]
pyrimidine-6-carboxamide MS-ESI (m/z): 480 [M + 1].sup.+ 61
##STR00071## 7-cyclopentyl-N,N-dimethyl-2-((5-((3S,5R)-3,4,5-tri-
methylpiperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-
d]pyrimidine-6-carboxamide MS-ESI (m/z): 494 [M + 1].sup.+ 62
##STR00072## 7-cyclopentyl-2-((5-((3S,5R)-4-ethyl-3,5-dimethyl-
piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethylthieno
[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 508 [M + 1].sup.+ 63
##STR00073## 7-cyclopentyl-N,N-dimethyl-2-((5-(1-methyl-2,4-di-
oxo-1,3,8-triazaspiro[4.5]decan-8-yl)pyridin-2-yl)
amino)thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 549 [M +
1].sup.+ 64 ##STR00074##
2-((5-(4-carbamoyl-4-(methylamino)piperidin-1-yl)
pyridin-2-yl)amino)-7-cyclopentyl-N,N-dimethyl-
thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 523 [M +
1].sup.+
Examples 65-76 listed in Table 2 were prepared according to the
method described for Example 1, by replacing dimethylamine
hydrochloride with the corresponding amine, while Examples 77-84
were prepared according to the method described for Example 2. The
structures and names of Examples 65-84 are given in Table 2.
TABLE-US-00002 TABLE 2 EXAMPLE STRUCTURE NAME DATA 65 ##STR00075##
azetidin-1-yl(7-cyclopentyl-2-((5-(piperazin-1-yl)
pyridin-2-yl)amino)thieno[3,2-d]pyrimidin-6-yl)methanone MS-ESI
(m/z): 464 [M + 1].sup.+ 66 ##STR00076##
(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)
thieno[3,2-d]pyrimidin-6-yl)(3-methoxyazetidin-1-yl) methanone
MS-ESI (m/z): 494 [M + 1].sup.+ 67 ##STR00077##
(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)
thieno[3,2-d]pyrimidin-6-yl)(3-hydroxyazetidin-1-yl) methanone
MS-ESI (m/z): 480 [M + 1].sup.+ 68 ##STR00078##
(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)
thieno[3,2-d]pyrimidin-6-yl)(piperidin-1-yl)methanone MS-ESI (m/z):
492 [M + 1].sup.+ 69 ##STR00079##
(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)
thieno[3,2-d]pyrimidin-6-yl)(4-methylpiperaizn-1-yl) methanone
MS-ESI (m/z): 507 [M + 1].sup.+ 70 ##STR00080##
(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)
thieno[3,2-d]pyrimidin-6-yl)(piperazin-1-yl)methanone MS-ESI (m/z):
493 [M + 1].sup.+ 71 ##STR00081##
7-cyclopentyl-N-cyclopropyl-2-((5-(piperazin-1-yl)pyri-
din-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z):
464 [M + 1].sup.+ 72 ##STR00082##
(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)
thieno[3,2-d]pyrimidin-6-yl)(pyrrolidin-1-yl)methanone MS-ESI
(m/z): 478 [M + 1].sup.+ 73 ##STR00083##
7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)
thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 424 [M +
1].sup.+ 74 ##STR00084##
7-cyclopentyl-N-methyl-2-((5-(piperazin-1-yl)pyridin-
2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 438
[M + 1].sup.+ 75 ##STR00085##
7-cyclopentyl-N-ethyl-2-((5-(piperazin-1-yl)pyridin-2-
yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 452 [M
+ 1].sup.+ 76 ##STR00086##
(7-cyclopentyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)
thieno[3,2-d]pyrimidin-6-yl)(morpholino)methanone MS-ESI (m/z): 494
[M + 1].sup.+ 77 ##STR00087##
azetidin-1-yl(7-cyclopentyl-2-((5-(4-methylpiperazin-1-
yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidin-6-yl) methanone MS-ESI
(m/z): 478 [M + 1].sup.+ 78 ##STR00088##
(7-cyclopentyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-
yl)amino)thieno[3,2-d]pyrimidin-6-yl)(3-methoxy-
azetidin-1-yl)methanone MS-ESI (m/z): 508 [M + 1].sup.+ 79
##STR00089##
(7-cyclopentyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-
yl)amino)thieno[3,2-d]pyrimidin-6-yl)(piperidin-1-yl) methanone
MS-ESI (m/z): 506 [M + 1].sup.+ 80 ##STR00090##
(7-cyclopentyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-
yl)amino)thieno[3,2-d]pyrimidin-6-yl)(4-methylpipera-
zin-1-yl)methanone MS-ESI (m/z): 521 [M + 1].sup.+ 81 ##STR00091##
7-cyclopentyl-N-cyclopropyl-2-((5-(4-methylpiperazin-
1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6- carboxamide
MS-ESI (m/z): 478 [M + 1].sup.+ 82 ##STR00092##
(7-cyclopentyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-
yl)amino)thieno[3,2-d]pyrimidin-6-yl)(pyrrolidin-1-yl) methanone
MS-ESI (m/z): 492 [M + 1].sup.+ 83 ##STR00093##
7-cyclopentyl-N-methyl-2-((5-(4-methylpiperazin-1-yl)
pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6- carboxamide MS-ESI
(m/z): 452 [M + 1].sup.+ 84 ##STR00094##
(7-cyclopentyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-
yl)amino)thieno[3,2-d]pyrimidin-6-yl)(morpholino) methanone MS-ESI
(m/z): 508 [M + 1].sup.+
Example 85
N,N-dimethyl-7-((1r,4r)-4-methylcyclohexyl)-2-((5-(piperazin-1-yl)pyridin--
2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide (85)
##STR00095##
The title compound (Example 85) (10 mg, 98%) was prepared by using
the same procedure as described for Example 1 by replacing
cyclopentanecarbaldehyde with
(1r,4r)-4-methylcyclohexane-1-carbaldehyde. MS-ESI (m/z): 480
[M+1].sup.+.
Following essentially the same procedures outlined for Examples 85,
Examples 86-94 listed in Table 3 were prepared by replacing
tert-butyl 4-(6-formamidopyridin-3-yl)piperazine-1-carboxylate with
the corresponding aminopyridines or aminopyridazines and sequential
modifications as necessary, such as acylation and
TABLE-US-00003 TABLE 3 EXAMPLE STRUCTURE NAME DATA 86 ##STR00096##
N,N-dimethyl-7-((1r,4r)-4-methylcyclohexyl)-2-((5-
(4-methylpiperazin-1-yl)pyridin-2-yl)amino)thieno
[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 494 [M + 1].sup.+ 87
##STR00097## N,N-dimethyl-7-((1r,4r)-4-methylcyclohexyl)-2-
((5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino)
thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 451 [M +
1].sup.+ 88 ##STR00098##
N,N-dimethyl-2-((6-methyl-5,6,7,8-tetrahydro-1,6-
naphthyridin-2-yl)amino)-7-((1r,4r)-4-methylcyclo-
hexyl)thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 465 [M +
1].sup.+ 89 ##STR00099##
2-((6-acetyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)
amino)-N,N-dimethyl-7-((1r,4r)-4-methylcyclohexyl)
thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 493 [M +
1].sup.+ 90 ##STR00100##
2-((6-(2-hydroxyacetyl)-5,6,7,8-tetrahydro-1,6-
naphthyridin-2-yl)amino)-N,N-dimethyl-7-((1r,4r)-4-
methylcyclohexyl)thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI
(m/z): 509 [M + 1].sup.+ 91 ##STR00101##
N,N-dimethyl-7-((1r,4r)-4-methylcyclohexyl)-2-((6-
(piperazin-1-yl)pyridazin-3-yl)amino)thieno[3,2-d]
pyrimidine-6-carboxamide MS-ESI (m/z): 481 [M + 1].sup.+ 92
##STR00102## N,N-dimethyl-7-((1r,4r)-4-methylcyclohexyl)-2-((6-
(4-methylpiperazin-1-yl)pyridazin-3-yl)amino)thieno
[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 495 [M + 1].sup.+ 93
##STR00103## 2-((6-(4-acetylpiperazin-1-yl)pyridazin-3-yl)amino)-
N,N-dimethyl-7-((1r,4r)-4-methylcylcohexyl)thieno
[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 523 [M + 1].sup.+ 94
##STR00104## 2-((6-(4-(2-hydroxyacetyl)piperazin-1-yl)pyridazin-
3-yl)amino)-N,N-dimethyl-7-((1r,4r)-4-methyl-
cyclohexyl)thieno[3,2-d]pyrimidine-6-carboxamide MS-ESI (m/z): 539
[M + 1].sup.+
Cell Proliferation Assays
To investigate whether a compound is able to inhibit the activity
of CDK4/6 in cells, a mechanism-based assay using COLO-205 cell was
developed. In this assay, inhibition of CDK4/6 was detected by the
inhibition of COLO-205 cells proliferation. COLO-205 cells were
cultured in culture flasks to 40-80% confluence in RPMI-1640 plus
10% fetal bovine serum. Cells were collected and plated onto
96-well plates at desired cell density (2000 cells/well). Plates
were incubated overnight at 37.degree. C., with 5% CO.sub.2 to
adhere. Compounds were added to the plates, the final compound
concentrations were 10000, 3333.3, 1111.1, 270.4, 123.5, 41.2,
13.7, 4.6 and 1.5 nM. Place plates at 37.degree. C., with 5%
CO.sub.2 for 48 h. After removing the medium, 20 .mu.l MTS/100
.mu.l medium mixture solution were added to each well and incubate
the plates for exactly 1.5 hours. Stop the reaction by adding 25
.mu.l 10% SDS per well. Measure absorbance at 490 nm and 650 nm
(reference wavelength). IC.sub.50 was calculated using GraphPad
Prism 5.0.
BE(2)-C Cells were plated in 96-well plates with 150 .mu.l culture
medium at cell density of 5000 cells/well. Compounds dilution: 20
mM stock solution of all compounds in DMSO. On the day of
treatment, compounds were fresh diluted from the stock solution to
a working solution (4.times. of final concentrations) in culture
medium. 50 .mu.l of compound mixtures were added to duplicate wells
along with 150 .mu.l of cells. 24 hours after BE(2)-C cells were
plated, testing compounds were added. Cell proliferation was
measured by MTS assay following manufacturer's instruction after
compound treatment for 72 hours.
Select compounds prepared as described above were assayed according
to the biological procedures described herein. The results are
given in Table 4.
TABLE-US-00004 TABLE 4 Example COLO205 IC.sub.50 (nM) BE(2)-C
IC.sub.50 (nM) 1 1106 38.5 2 339 24.1 5 517 601 7 711 / 73 624 / 87
450 88 855 / 89 389 / 90 270 / 91 223 /
* * * * *